Author: "Jason S Iacovoni" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Jason S Iacovoni"' showing total 62 results

Start Over Author "Jason S Iacovoni"

62 results on '"Jason S Iacovoni"'

1. Transfer of dysbiotic gut microbiota has beneficial effects on host liver metabolism

Author: Simon Nicolas, Vincent Blasco‐Baque, Audren Fournel, Jerome Gilleron, Pascale Klopp, Aurelie Waget, Franck Ceppo, Alysson Marlin, Roshan Padmanabhan, Jason S Iacovoni, François Tercé, Patrice D Cani, Jean‐François Tanti, Remy Burcelin, Claude Knauf, Mireille Cormont, and Matteo Serino
Subjects: gut microbiota transfer, hepatic glucose production, high‐fat diet, metabolic diseases, microbiome, Biology (General), QH301-705.5, Medicine (General), R5-920
Abstract: Abstract Gut microbiota dysbiosis has been implicated in a variety of systemic disorders, notably metabolic diseases including obesity and impaired liver function, but the underlying mechanisms are uncertain. To investigate this question, we transferred caecal microbiota from either obese or lean mice to antibiotic‐free, conventional wild‐type mice. We found that transferring obese‐mouse gut microbiota to mice on normal chow (NC) acutely reduces markers of hepatic gluconeogenesis with decreased hepatic PEPCK activity, compared to non‐inoculated mice, a phenotypic trait blunted in conventional NOD2 KO mice. Furthermore, transferring of obese‐mouse microbiota changes both the gut microbiota and the microbiome of recipient mice. We also found that transferring obese gut microbiota to NC‐fed mice then fed with a high‐fat diet (HFD) acutely impacts hepatic metabolism and prevents HFD‐increased hepatic gluconeogenesis compared to non‐inoculated mice. Moreover, the recipient mice exhibit reduced hepatic PEPCK and G6Pase activity, fed glycaemia and adiposity. Conversely, transfer of lean‐mouse microbiota does not affect markers of hepatic gluconeogenesis. Our findings provide a new perspective on gut microbiota dysbiosis, potentially useful to better understand the aetiology of metabolic diseases.
Published: 2017
Full Text: View/download PDF

2. Determinants of human adipose tissue gene expression: impact of diet, sex, metabolic status, and cis genetic regulation.

Author: Nathalie Viguerie, Emilie Montastier, Jean-José Maoret, Balbine Roussel, Marion Combes, Carine Valle, Nathalie Villa-Vialaneix, Jason S Iacovoni, J Alfredo Martinez, Claus Holst, Arne Astrup, Hubert Vidal, Karine Clément, Jorg Hager, Wim H M Saris, and Dominique Langin
Subjects: Genetics, QH426-470
Abstract: Weight control diets favorably affect parameters of the metabolic syndrome and delay the onset of diabetic complications. The adaptations occurring in adipose tissue (AT) are likely to have a profound impact on the whole body response as AT is a key target of dietary intervention. Identification of environmental and individual factors controlling AT adaptation is therefore essential. Here, expression of 271 transcripts, selected for regulation according to obesity and weight changes, was determined in 515 individuals before, after 8-week low-calorie diet-induced weight loss, and after 26-week ad libitum weight maintenance diets. For 175 genes, opposite regulation was observed during calorie restriction and weight maintenance phases, independently of variations in body weight. Metabolism and immunity genes showed inverse profiles. During the dietary intervention, network-based analyses revealed strong interconnection between expression of genes involved in de novo lipogenesis and components of the metabolic syndrome. Sex had a marked influence on AT expression of 88 transcripts, which persisted during the entire dietary intervention and after control for fat mass. In women, the influence of body mass index on expression of a subset of genes persisted during the dietary intervention. Twenty-two genes revealed a metabolic syndrome signature common to men and women. Genetic control of AT gene expression by cis signals was observed for 46 genes. Dietary intervention, sex, and cis genetic variants independently controlled AT gene expression. These analyses help understanding the relative importance of environmental and individual factors that control the expression of human AT genes and therefore may foster strategies aimed at improving AT function in metabolic diseases.
Published: 2012
Full Text: View/download PDF

3. Cohesin protects genes against γH2AX Induced by DNA double-strand breaks.

Author: Pierre Caron, Francois Aymard, Jason S Iacovoni, Sébastien Briois, Yvan Canitrot, Beatrix Bugler, Laurent Massip, Ana Losada, and Gaëlle Legube
Subjects: Genetics, QH426-470
Abstract: Chromatin undergoes major remodeling around DNA double-strand breaks (DSB) to promote repair and DNA damage response (DDR) activation. We recently reported a high-resolution map of γH2AX around multiple breaks on the human genome, using a new cell-based DSB inducible system. In an attempt to further characterize the chromatin landscape induced around DSBs, we now report the profile of SMC3, a subunit of the cohesin complex, previously characterized as required for repair by homologous recombination. We found that recruitment of cohesin is moderate and restricted to the immediate vicinity of DSBs in human cells. In addition, we show that cohesin controls γH2AX distribution within domains. Indeed, as we reported previously for transcription, cohesin binding antagonizes γH2AX spreading. Remarkably, depletion of cohesin leads to an increase of γH2AX at cohesin-bound genes, associated with a decrease in their expression level after DSB induction. We propose that, in agreement with their function in chromosome architecture, cohesin could also help to isolate active genes from some chromatin remodelling and modifications such as the ones that occur when a DSB is detected on the genome.
Published: 2012
Full Text: View/download PDF

4. Notch activation shifts the fate decision of senescent progenitors toward myofibrogenesis in human adipose tissue

Author: Nathalie Boulet, Anaïs Briot, Valentin Jargaud, David Estève, Anne Rémaury, Chloé Belles, Pénélope Viana, Jessica Fontaine, Lucie Murphy, Catherine Déon, Marie Guillemot, Catherine Pech, Yaligara Veeranagouda, Michel Didier, Pauline Decaunes, Etienne Mouisel, Christian Carpéné, Jason S. Iacovoni, Alexia Zakaroff‐Girard, Jean‐Louis Grolleau, Jean Galitzky, Séverine Ledoux, Jean‐Claude Guillemot, Anne Bouloumié, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), SANOFI Recherche, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and boulet, nathalie
Subjects: [SDV] Life Sciences [q-bio], obesity, Aging, senescence, [SDV]Life Sciences [q-bio], Cell Biology, NOTCH signaling, myofibrogenesis, adipogenesis, adipose tissue, progenitors
Abstract: International audience; Senescence is a key event in the impairment of adipose tissue (AT) function with obesity and aging but the underlying molecular and cellular players remain to be fully defined, particularly with respect to the human AT progenitors. We have found distinct profiles of senescent progenitors based on AT location between stroma from visceral versus subcutaneous AT. In addition to flow cytometry, we characterized the location differences with transcriptomic and proteomic approaches, uncovering the genes and developmental pathways that are underlying replicative senescence. We identified key components to include INBHA as well as SFRP4 and GREM1, antagonists for the WNT and BMP pathways, in the senescence-associated secretory phenotype and NOTCH3 in the senescence-associated intrinsic phenotype. Notch activation in AT progenitors inhibits adipogenesis and promotes myofibrogenesis independently of TGFβ. In addition, we demonstrate that NOTCH3 is enriched in the premyofibroblast progenitor subset, which preferentially accumulates in the visceral AT of patients with an early obesity trajectory. Herein, we reveal that NOTCH3 plays a role in the balance of progenitor fate determination preferring myofibrogenesis at the expense of adipogenesis. Progenitor NOTCH3 may constitute a tool to monitor replicative senescence and to limit AT dysfunction in obesity and aging.
Published: 2022
Full Text: View/download PDF

5. Nuclear HMGB1 protects from nonalcoholic fatty liver disease through negative regulation of liver X receptor

Author: Jean Personnaz, Enzo Piccolo, Alizée Dortignac, Jason S. Iacovoni, Jérôme Mariette, Vincent Rocher, Arnaud Polizzi, Aurélie Batut, Simon Deleruyelle, Lucas Bourdens, Océane Delos, Lucie Combes-Soia, Romain Paccoud, Elsa Moreau, Frédéric Martins, Thomas Clouaire, Fadila Benhamed, Alexandra Montagner, Walter Wahli, Robert F. Schwabe, Armelle Yart, Isabelle Castan-Laurell, Justine Bertrand-Michel, Odile Burlet-Schiltz, Catherine Postic, Pierre-Damien Denechaud, Cédric Moro, Gaelle Legube, Chih-Hao Lee, Hervé Guillou, Philippe Valet, Cédric Dray, Jean-Philippe Pradère, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), SIAAP - Direction du Développement et de la Prospective, SIAAP, Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), ToxAlim (ToxAlim), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de pharmacologie et de biologie structurale (IPBS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Unité de biologie moléculaire, cellulaire et du développement - UMR5077 (MCD), Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Lee Kong Chian School of Medicine, Nanyang Technological University [Singapour], Columbia University [New York], MetaToul FluxoMet (TBI-MetaToul), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Harvard T.H. Chan School of Public Health, This study was supported by grants from INSERM, Paul Sabatier University, the Agence Nationale de la Recherche (ANR-17-CE14-0016, to J.-P.P.), and the Région Occitanie and Association Française d’Etude et de Recherche sur l’Obésité (to J.-P.P.). J.P. was supported by a scholarship from Paul Sabatier University. E.P. was supported by a scholarship from Agence Nationale de la Recherche (ANR-17-CE14-0016). R.P. was supported by a scholarship from Région Midi-Pyrénées-INSERM (no. 15050341). O.B.-S. and L.C.-S. and the proteomic facility were supported, in part, by the Région Occitanie, European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research with the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08), ANR-17-CE14-0016,HOLISTic,Rôle de la protéine HMGB1 au cours du stress metabolique(2017), and Lee Kong Chian School of Medicine (LKCMedicine)
Subjects: Fatty Liver, Multidisciplinary, [SDV]Life Sciences [q-bio], Medicine [Science], chemical and pharmacologic phenomena, Lipid Metabolisms
Abstract: Dysregulations of lipid metabolism in the liver may trigger steatosis progression, leading to potentially severe clinical consequences such as nonalcoholic fatty liver diseases (NAFLDs). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis. Mice with liver-specific Hmgb1 deficiency display exacerbated liver steatosis, while Hmgb1-overexpressing mice exhibited a protection from fatty liver progression when subjected to nutritional stress. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα and PPARγ activity. HMGB1 repression is not mediated through nucleosome landscape reorganization but rather via a preferential DNA occupation in a region carrying genes regulated by LXRα and PPARγ. Together, these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target the LXRα-PPARγ axis during NAFLD. Published version This study was supported by grants from INSERM, Paul Sabatier University, the Agence Nationale de la Recherche (ANR-17-CE14-0016, to J.-P.P.), and the Région Occitanie and Association Française d’Etude et de Recherche sur l’Obésité (to J.-P.P.). J.P. was supported by a scholarship from Paul Sabatier University. E.P. was supported by a scholarship from Agence Nationale de la Recherche (ANR-17-CE14-0016). R.P. was supported by a scholarship from Région Midi-Pyrénées-INSERM (no. 15050341). O.B.-S. and L.C.-S. and the proteomic facility were supported, in part, by the Région Occitanie, European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research with the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08).
Published: 2022
Full Text: View/download PDF

6. Proteomics reveals long-term alterations in signaling and metabolic pathways following both myocardial infarction and chemically induced denervation

Author: Jennifer Ben Salem, Jason S. Iacovoni, Denis Calise, Dina N. Arvanitis, Francis Beaudry, ARVANITIS, Dina N, Université de Montréal (UdeM), Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional d'Exploration Fonctionnelle et Ressources Expérimentales (CREFRE), and Université de Montréal. Faculté de médecine vétérinaire
Subjects: Transient receptor potential vanillId subtype 1 (TRPV1) (TRPV1), [SCCO.NEUR]Cognitive science/Neuroscience, autonomic nervous system, [SCCO.NEUR] Cognitive science/Neuroscience, heart failure, integrative biology, General Medicine, bioinformatics, resiniferatoxin (RTX), Transient receptor potential vanilloid subtype 1 (TRPV1) (TRPV1), Denervation, Biochemistry, Disease Models, Animal, Mice, Cellular and Molecular Neuroscience, myocardial infarction, proteomics, Animals, Metabolic Networks and Pathways, Signal Transduction, mass spectrometry
Abstract: International audience; Myocardial infraction (MI) is the principal risk factor for the onset of heart failure (HF). Investigations regarding the physiopathology of MI progression to HF have revealed the concerted engagement of other tissues, such as the autonomic nervous system and the medulla oblongata (MO), giving rise to systemic effects, important in the regulation of heart function. Cardiac sympathetic afferent denervation following application of resiniferatoxin (RTX) attenuates cardiac remodelling and restores cardiac function following MI. While the physiological responses are well documented in numerous species, the underlying molecular responses during the initiation and progression from MI to HF remains unclear. We obtained multi-tissue time course proteomics with a murine model of HF induced by MI in conjunction with RTX application. We isolated tissue sections from the left ventricle (LV), MO, cervical spinal cord and cervical vagal nerves at four time points over a 12-week study. Bioinformatic analyses consistently revealed a high statistical enrichment for metabolic pathways in all tissues and treatments, implicating a central role of mitochondria in the tissue-cellular response to both MI and RTX. In fact, the additional functional pathways found to be enriched in these tissues, involving the cytoskeleton, vesicles and signal transduction, could be downstream of responses initiated by mitochondria due to changes in neuronal pulse frequency after a shock such as MI or the modification of such frequency communication from the heart to the brain after RTX application. Development of future experiments, based on our proteomic results, should enable the dissection of more precise mechanisms whereby metabolic changes in neuronal and cardiac tissues can effectively ameliorate the negative physiological effects of MI via RTX application.
Published: 2022
Full Text: View/download PDF

7. Hepatocyte nuclear factor-1β shapes the energetic homeostasis of kidney tubule cells

Author: Alexis Piedrafita, Stanislas Faguer, Benjamin Breuil, Stéphane Decramer, Dominique Chauveau, Joost P. Schanstra, Myriam Malet-Martino, Stéphane Balayssac, Jean-Sébastien Saulnier-Blache, Jason S. Iacovoni, Alexandre Lucas, Audrey Casemayou, Institut National de la Santé et de la Recherche Médicale - INSERM, Interactions moléculaires et réactivité chimique et photochimique (IMRCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Néphrologie et Immunopathologie Clinique, Centre Hospitalier Universitaire de Toulouse, PRES Université de Toulouse, CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Centre de Référence du Sud Ouest des Maladies Rénales Rares, Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique (SPCMIB), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Fluides, Energie, Réacteurs, Matériaux et Transferts (FERMAT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), BIBAC - Chimie analytique et interactions biomolécules - matière molle biomimétique (BIBAC), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), and Saulnier-Blache, Jean Sébastien
Subjects: Choline kinase, Cell Survival, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, HNF-1β, Biochemistry, Cell Line, Kidney Tubules, Proximal, 03 medical and health sciences, Gene Knockout Techniques, Mice, 0302 clinical medicine, Genetics, medicine, [CHIM]Chemical Sciences, Animals, Homeostasis, Humans, Glycolysis, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, Hepatocyte Nuclear Factor 1-beta, 0303 health sciences, Kidney, kidney tubule, Chemistry, hypoxia, metabolism, Epithelial Cells, Metabolism, Acute Kidney Injury, Cell Hypoxia, Cell biology, Citric acid cycle, [SDV] Life Sciences [q-bio], Hepatocyte nuclear factors, Cytosol, medicine.anatomical_structure, Gene Expression Regulation, Metabolome, CRISPR-Cas Systems, Transcriptome, Gene Deletion, Biotechnology, Signal Transduction
Abstract: International audience; Energetic metabolism controls key steps of kidney development, homeostasis, and epithelial repair following acute kidney injury (AKI). Hepatocyte nuclear factor-1β (HNF-1β) is a master transcription factor that controls mitochondrial function in proximal tubule (PT) cells. Patients with HNF1B pathogenic variant display a wide range of kidney developmental abnormalities and progressive kidney fibrosis. Characterizing the metabolic changes in PT cells with HNF-1β deficiency may help to identify new targetable molecular hubs involved in HNF1B-related kidney phenotypes and AKI. Here, we combined 1 H-NMR-based metabolomic analysis in a murine PT cell line with CrispR/Cas9-induced Hnf1b invalidation (Hnf1b-/- ), clustering analysis, targeted metabolic assays, and datamining of published RNA-seq and ChIP-seq dataset to identify the role of HNF-1β in metabolism. Hnf1b-/- cells grown in normoxic conditions display intracellular ATP depletion, increased cytosolic lactate concentration, increased lipid droplet content, failure to use pyruvate for energetic purposes, increased levels of tricarboxylic acid (TCA) cycle intermediates and oxidized glutathione, and a reduction of TCA cycle byproducts, all features consistent with mitochondrial dysfunction and an irreversible switch toward glycolysis. Unsupervised clustering analysis showed that Hnf1b-/- cells mimic a hypoxic signature and that they cannot furthermore increase glycolysis-dependent energetic supply during hypoxic challenge. Metabolome analysis also showed alteration of phospholipid biosynthesis in Hnf1b-/- cells leading to the identification of Chka, the gene coding for choline kinase α, as a new putative target of HNF-1β. HNF-1β shapes the energetic metabolism of PT cells and HNF1B deficiency in patients could lead to a hypoxia-like metabolic state precluding further adaptation to ATP depletion following AKI.
Published: 2021
Full Text: View/download PDF

8. Nuclear HMGB1 protects from non-alcoholic fatty liver diseases through negative regulation of liver X receptor

Author: Romain Paccoud, Arnaud Polizzi, Isabelle Castan-Laurell, Jérôme Mariette, Robert F. Schwabe, W. Wahli, Frédéric Martins, Jason S. Iacovoni, Enzo Piccolo, Thomas Clouaire, Simon Deleruyelle, Chih-Hao Lee, Philippe Valet, Jean-Philippe Pradere, Gaëlle Legube, Fadila Benhamed, Hervé Guillou, Alexandra Montagner, Cedric Moro, Catherine Postic, Jean Personnaz, Elsa Moreau, Cédric Dray, Alizee Dortignac, Armelle Yart, and Aurélie Batut
Subjects: medicine.medical_specialty, Fatty liver, chemical and pharmacologic phenomena, Lipid metabolism, Biology, medicine.disease, Transcriptome, Endocrinology, Insulin resistance, Internal medicine, Lipogenesis, medicine, Steatosis, Liver X receptor, Transcription factor
Abstract: Dysregulations of lipid metabolism in the liver may trigger steatosis progression leading to potentially severe clinical consequences such as non-alcoholic fatty liver diseases (NAFLD). Molecular mechanisms underlying liver lipogenesis are very complex and fine-tuned by chromatin dynamics and the activity of multiple key transcription factors. Here, we demonstrate that the nuclear factor HMGB1 acts as a strong repressor of liver lipogenesis during metabolic stress in NAFLD. Mice with liver-specific Hmgb1-deficiency display exacerbated liver steatosis and hepatic insulin resistance when subjected to a high-fat diet or after fasting/refeeding. Global transcriptome and functional analysis revealed that the deletion of Hmgb1 gene enhances LXRα activity resulting in increased lipogenesis. HMGB1 repression is not mediated through nucleosome landscape re-organization but rather via a preferential DNA occupation in region carrying genes regulated by LXRα. Together these findings suggest that hepatocellular HMGB1 protects from liver steatosis development. HMGB1 may constitute a new attractive option to therapeutically target LXRα axis during NAFLD.
Published: 2021
Full Text: View/download PDF

9. GeneHuggers: database mining and application connectivity tools for subsequence analyses of the human genome.

Author: Jason S. Iacovoni
Published: 2003
Full Text: View/download PDF

10. Kidney inflammaging is promoted by CCR2

Author: Lise, Lefèvre, Jason S, Iacovoni, Hélène, Martini, Julie, Bellière, Damien, Maggiorani, Marianne, Dutaur, Dimitri J, Marsal, Pauline, Decaunes, Nathalie, Pizzinat, Jeanne, Mialet-Perez, Daniel, Cussac, Angelo, Parini, and Victorine, Douin-Echinard
Subjects: Inflammation, Male, Aging, Receptors, CCR2, Macrophages, CX3C Chemokine Receptor 1, Mesenchymal stromal cells, Kidney, Senescence, Inflammaging, Monocytes, Mice, Inbred C57BL, Mice, Cellular Microenvironment, CD73, Animals, Cytokines, CCR2, Original Article, Cellular Senescence
Abstract: The incidence of disorders associated with low inflammatory state, such as chronic kidney disease, increases in the elderly. The accumulation of senescent cells during aging and the senescence-associated secretory phenotype, which leads to inflammaging, is known to be deleterious and account for progressive organ dysfunction. To date, the cellular actors implicated in chronic inflammation in the kidney during aging are still not well characterized. Using the DECyt method, based on hierarchical clustering of flow cytometry data, we showed that aging was associated with significant changes in stromal cell diversity in the kidney. In particular, we identified two cell populations up-regulated with aging, the mesenchymal stromal cell subset (kMSC) expressing CD73 and the monocyte-derived Ly6C+ CCR2+ macrophage subset expressing pro-inflammatory cytokines. Aged CD73+ kMSCs depicted senescence associated features with low proliferation rate, increased DNA damage foci and Ccl2 expression. Using co-cultures experiments, we showed that aged CD73+ kMSC promoted monocyte activation and secretion of inflammatory cytokines albeit less efficiently than young CD73+ kMSCs. In the context of ageing, increased frequency of CD73+ kMSC subpopulations could provide additional niche factors to newly recruited monocytes favoring a positive regulatory loop in response to local inflammation. Interfering with such partnership during aging could be a valuable approach to regulate kidney inflammaging and to limit the risk of developing chronic kidney disease in the elderly. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-020-03719-0.
Published: 2020

11. Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes

Author: Krzysztof Ginalski, François Aymard, Marion Aguirrebengoa, Peter Fraser, Magdalena Skrzypczak, Emmanuelle Guillou, Jason S. Iacovoni, Anna Biernacka, Coline Arnould, Béatrix Bugler, Vincent Rocher, Biola M. Javierre, Gaëlle Legube, and Maga Rowicka
Subjects: DNA Replication, 0301 basic medicine, DNA Repair, Transcription, Genetic, DNA repair, translocation, Biology, Models, Biological, DSB repair, Genome, Article, Cell Line, Histones, Capture Hi-C, Chromosome conformation capture, 03 medical and health sciences, Protein Domains, Structural Biology, Cluster Analysis, Humans, DNA Breaks, Double-Stranded, RNA, Small Interfering, Molecular Biology, Gene, Recombination, Genetic, Genetics, Genome, Human, G1 Phase, DNA replication, Chromosome Mapping, Nuclear Proteins, Cell biology, Tamoxifen, 030104 developmental biology, MRN complex, DNA, Intergenic, Human genome, transcription, Homologous recombination, clustering
Abstract: The ability of DNA double-strand breaks (DSBs) to cluster in mammalian cells has been a subject of intense debate in recent years. Here we used a high-throughput chromosome conformation capture assay (capture Hi-C) to investigate clustering of DSBs induced at defined loci in the human genome. The results unambiguously demonstrated that DSBs cluster, but only when they are induced within transcriptionally active genes. Clustering of damaged genes occurs primarily during the G1 cell-cycle phase and coincides with delayed repair. Moreover, DSB clustering depends on the MRN complex as well as the Formin 2 (FMN2) nuclear actin organizer and the linker of nuclear and cytoplasmic skeleton (LINC) complex, thus suggesting that active mechanisms promote clustering. This work reveals that, when damaged, active genes, compared with the rest of the genome, exhibit a distinctive behavior, remaining largely unrepaired and clustered in G1, and being repaired via homologous recombination in postreplicative cells.
Published: 2017
Full Text: View/download PDF

12. Yellow adipocytes comprise a new adipocyte sub-type present in human bone marrow

Author: Philippe Valet, Jill Corre, Mohamed Moutahir, Camille Attané, Jason S. Iacovoni, Nicolas Reina, Karima Chaoui, David Estève, Catherine Muller, and Odile Schiltz
Subjects: medicine.medical_specialty, biology, Chemistry, Lipid metabolism, Metabolism, In vitro, Monoacylglycerol lipase, chemistry.chemical_compound, medicine.anatomical_structure, Endocrinology, Internal medicine, Adipocyte, medicine, biology.protein, Lipolysis, Bone marrow, Lipase
Abstract: During energy demanding conditions, white adipocytes store triglycerides and release fatty acids through lipolysis. In contrast, bone marrow adipocytes (BM-Ad) increase in size during caloric restriction, suggesting this fat depot exhibits precise metabolic specificity. We found subcutaneous adipocytes (SC-Ad) and BM-Ad share morphological features, but possess distinct lipid metabolism. BM-Ad show enrichment in cholesterol-oriented metabolism that correlates with increased free cholesterol content, while proteins involved in lipolysis were downregulated. A strong down-regulation in expression of monoacylglycerol (MG) lipase was observed leading to an accumulation of major MG species and accordingly the basal and induced lipolytic responses were absent in BM-Ad. These features are not recapitulatedin vitrousing differentiated bone marrow mesenchymal stem cells. Since our data demonstrate that BM-Ad comprise a distinct class of adipocytes, we propose renaming them yellow adipocytes.
Published: 2019
Full Text: View/download PDF

13. Human Bone Marrow Is Comprised of Adipocytes with Specific Lipid Metabolism

Author: Philippe Valet, Mohamed Moutahir, Camille Attané, Jason S. Iacovoni, Karima Chaoui, Jill Corre, Nicolas Reina, David Estève, Odile Schiltz, Catherine Muller, ORANGE, Colette, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées
Subjects: Proteomics, 0301 basic medicine, medicine.medical_specialty, Proteome, Lipolysis, [SDV]Life Sciences [q-bio], Adipose tissue, General Biochemistry, Genetics and Molecular Biology, Cell Line, Mice, 03 medical and health sciences, chemistry.chemical_compound, Basal (phylogenetics), 0302 clinical medicine, Microscopy, Electron, Transmission, Bone Marrow, Internal medicine, Adipocytes, medicine, Animals, Humans, Protein Interaction Maps, lcsh:QH301-705.5, Cells, Cultured, Caloric Restriction, Chemistry, Cholesterol, Lipid metabolism, Metabolism, Lipid Metabolism, Monoacylglycerol Lipases, [SDV] Life Sciences [q-bio], Monoacylglycerol lipase, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, lcsh:Biology (General), Bone marrow, 030217 neurology & neurosurgery
Abstract: Summary: Under caloric restriction, bone marrow adipocytes (BM-Ads) do not decrease in size compared to white adipocytes, suggesting they harbor unique metabolic properties. We compare human primary BM-Ads with paired subcutaneous adipocytes (SC-Ads) using proteomic and lipidomic approaches. We find that, although SC-Ads and BM-Ads share similar morphological features, they possess distinct lipid metabolism. Although BM-Ad shows enrichment in proteins involved in cholesterol metabolism, correlating with increased free cholesterol content, proteins involved in lipolysis were downregulated. In particular, monoacylglycerol lipase expression is strongly reduced in BM-Ads, leading to monoacylglycerol accumulation. Consequently, basal and induced lipolytic responses are absent in BM-Ads, affirming their differences in metabolic fitness upon caloric restriction. These specific metabolic features are not recapitulated in vitro using common protocols to differentiate bone marrow mesenchymal stem cells. Thus, contrary to classical SC-Ads, BM-Ads display a specific lipid metabolism, as they are devoid of lipolytic activity and exhibit a cholesterol-orientated metabolism. : Attané et al. show that, although human bone marrow adipocytes (BM-Ads) resemble classic white adipocytes on a morphological level, their lipid metabolism is highly specific. They are devoid of lipolytic activity, one of the main metabolic functions of white adipocytes, which explains why they behave like a preserved lipid source under energy-demanding conditions. Keywords: bone marrow adipocytes, cholesterol, lipolysis, monoacylglycerol lipase, proteomic, adipose tissue, bone marrow fat
Published: 2020
Full Text: View/download PDF

14. G-quadruplex aptamer selection using capillary electrophoresis-LED-induced fluorescence and Illumina sequencing

Author: Laurent Paquereau, Varravaddheay Ong-Meang, Audrey Ric, Vincent Ecochard, François Couderc, Audrey Boutonnet, Jason S. Iacovoni, Véréna Poinsot, Frédéric Ginot, Interactions moléculaires et réactivité chimique et photochimique (IMRCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Picometrics Technologies, Department of Telematics, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Fédération de Recherche Fluides, Energie, Réacteurs, Matériaux et Transferts (FERMAT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), BIBAC - Chimie analytique et interactions biomolécules - matière molle biomimétique (BIBAC), and Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT)
Subjects: Aptamer, 02 engineering and technology, G-quadruplex, 01 natural sciences, Biochemistry, Analytical Chemistry, chemistry.chemical_compound, Capillary electrophoresis, [CHIM]Chemical Sciences, A-DNA, Illumina dye sequencing, ComputingMilieux_MISCELLANEOUS, Gene Library, Base Sequence, SELEX Aptamer Technique, 010401 analytical chemistry, Thrombin, Electrophoresis, Capillary, High-Throughput Nucleotide Sequencing, Aptamers, Nucleotide, 021001 nanoscience & nanotechnology, Molecular biology, Fluorescence, 0104 chemical sciences, G-Quadruplexes, chemistry, 0210 nano-technology, DNA
Abstract: One of the major difficulties that arises when selecting aptamers containing a G-quadruplex is the correct amplification of the ssDNA sequence. Can aptamers containing a G-quadruplex be selected from a degenerate library using non-equilibrium capillary electrophoresis (CE) of equilibrium mixtures (NECEEM) along with high-throughput Illumina sequencing? In this article, we present some mismatches of the G-quadruplex T29 aptamer specific to thrombin, which was PCR amplified and sequenced by Illumina sequencing. Then, we show the proportionality between the number of sequenced molecules of T29 added to the library and the number of sequences obtained in Illumina sequencing, and we find that T29 sequences from this aptamer can be detected in a random library of ssDNA after the sample is fractionated by NECEEM, amplified by PCR, and sequenced. Treatment of the data by the counting of double-stranded DNA T29 sequences containing a maximum of two mismatches reveals a good correlation with the enrichment factor (fE). This factor is the ratio of the number of aptamer sequences found in the collected complex sample divided by the total number of sequencing reads (aptamer and non-aptamer) plus the quantity of T29 molecules (spiked into a DNA library) injected into CE.
Published: 2018
Full Text: View/download PDF

15. Caloric Restriction and Diet-Induced Weight Loss Do Not Induce Browning of Human Subcutaneous White Adipose Tissue in Women and Men with Obesity

Author: Valentin Barquissau, Frédéric Martins, Ez-Zoubir Amri, Cedric Moro, Jean-José Maoret, Sébastien Déjean, Nathalie Viguerie, Arne Astrup, Didier F. Pisani, Diane Beuzelin, Jason S. Iacovoni, Dominique Langin, Wim H. M. Saris, Benjamin Léger, Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Plateforme GeT (Génome et Transcriptome), Génopole Toulouse, Institut National de la Recherche Agronomique (INRA), Institute of Developmental Biology and Cancer (IBDC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (IBV), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, NUTRIM, Department of Nutrition, Exercise and Sports [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Mathématiques de Toulouse UMR5219 (IMT), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacologie Clinique, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie clinique, CHU Toulouse [Toulouse], Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Génome et Transcriptome - Plateforme Génomique (GeT-PlaGe), Institut National de la Recherche Agronomique (INRA)-Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Service Pharmacologie Clinique [CHU Toulouse], Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Humane Biologie, Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Adipose tissue, PROTEIN, White adipose tissue, BEIGE ADIPOCYTES, MOUSE, Mice, 0302 clinical medicine, FUNCTIONAL-CHARACTERIZATION, Weight loss, [MATH.MATH-ST]Mathematics [math]/Statistics [math.ST], insulin resistance, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, browning of white fat, Thermogenin, Very low calorie diet, RESTING ENERGY-EXPENDITURE, VISCERAL FAT, subcutaneous abdominal white adipose tissue, caloric restriction, medicine.symptom, medicine.medical_specialty, Diet, Reducing, Adipose Tissue, White, uncoupling protein 1, sex difference, food.diet, Subcutaneous Fat, 030209 endocrinology & metabolism, DISTINCT, METABOLISM, ADULT HUMANS, General Biochemistry, Genetics and Molecular Biology, human obesity, 03 medical and health sciences, food, Insulin resistance, dietary intervention, Internal medicine, Weight Loss, medicine, Animals, Humans, Resting energy expenditure, Obesity, business.industry, medicine.disease, 030104 developmental biology, Endocrinology, lcsh:Biology (General), CELLS, business
Abstract: Summary Caloric restriction (CR) is standard lifestyle therapy in obesity management. CR-induced weight loss improves the metabolic profile of individuals with obesity. In mice, occurrence of beige fat cells in white fat depots favors a metabolically healthy phenotype, and CR promotes browning of white adipose tissue (WAT). Here, human subcutaneous abdominal WAT samples were analyzed in 289 individuals with obesity following a two-phase dietary intervention consisting of an 8 week very low calorie diet and a 6-month weight-maintenance phase. Before the intervention, we show sex differences and seasonal variation, with higher expression of brown and beige markers in women with obesity and during winter, respectively. The very low calorie diet resulted in decreased browning of subcutaneous abdominal WAT. During the whole dietary intervention, evolution of body fat and insulin resistance was independent of changes in brown and beige fat markers. These data suggest that diet-induced effects on body fat and insulin resistance are independent of subcutaneous abdominal WAT browning in people with obesity.
Published: 2018
Full Text: View/download PDF

16. Crosstalk Between One Carbon Metabolism and Eph Signaling Promotes Neural Stem Cells Differentiation Through Epigenetic Remodeling

Author: Mohamad-Ali Fawal, Alice Davy, Christophe Audouard, Jason S. Iacovoni, Thomas Jungas, and Anthony Kischel
Subjects: 0303 health sciences, Cell, Erythropoietin-producing hepatocellular (Eph) receptor, Biology, Neural stem cell, Cell biology, 03 medical and health sciences, Crosstalk (biology), 0302 clinical medicine, medicine.anatomical_structure, medicine, Ephrin, Epigenetics, Stem cell, Developmental biology, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: SUMMARYMetabolic pathways, once seen as a mere consequence of cell states, have emerged as active players in dictating different cellular events such as proliferation, self-renewal and differentiation. Several studies have reported a role for folate-dependent 1-carbon (1C) metabolism in stem cells, however, its exact mode of action and how it interacts with other cues is largely unknown. Here, we report a link between the Eph:ephrin cell-cell communication pathway and 1C metabolism in controlling differentiation of neural stem cells. Transcriptional and functional analyses following ephrin stimulation revealed alterations in folate metabolism-related genes and enzymatic activity. In vitro and in vivo data indicate that Eph-B forward signaling alters the methylation state of H3K4 by regulating 1C metabolism, and locks neural stem cells in a differentiation-ready state. The functional link between cell-cell communication, metabolism and epigenetic remodeling identifies a novel triad in the control of stem cell self-renewal vs. differentiation.HIGHLIGHTS1C folate metabolism is regulated by local cell-to-cell communicationDescription of Eph-B transcriptional response in NSCEph activation decreases the expression and activity of DHFRInhibition of DHFR modifies epigenetic marks and impairs self-renewal of neural stem cellsDecreased H3K4 methylation locks neural stem cells in a pro-differentiation stateeTOC BLURBFawal et al. present evidence that Eph-B forward signaling inhibits 1C folate metabolism in neural stem cells leading to alteration of H3K4 methylation on key progenitor genes. In addition, they show that these epigenetic changes are inherited and maintained in the long term, thus locking NSC into a differentiation ready state.
Published: 2017
Full Text: View/download PDF

17. Cross Talk between One-Carbon Metabolism, Eph Signaling, and Histone Methylation Promotes Neural Stem Cell Differentiation

Author: Mohamad-Ali, Fawal, Thomas, Jungas, Anthony, Kischel, Christophe, Audouard, Jason S, Iacovoni, and Alice, Davy
Subjects: Histones, Mice, Inbred C57BL, Tetrahydrofolate Dehydrogenase, Neural Stem Cells, Inheritance Patterns, Animals, Cell Differentiation, Ephrins, Methylation, Proto-Oncogene Proteins c-akt, Carbon, Epigenesis, Genetic, Signal Transduction
Abstract: Metabolic pathways, once seen as a mere consequence of cell states, have emerged as active players in dictating different cellular events such as proliferation, self-renewal, and differentiation. Several studies have reported a role for folate-dependent one-carbon (1C) metabolism in stem cells; however, its exact mode of action and how it interacts with other cues are largely unknown. Here, we report a link between the Eph:ephrin cell-cell communication pathway and 1C metabolism in controlling neural stem cell differentiation. Transcriptional and functional analyses following ephrin stimulation revealed alterations in folate metabolism-related genes and enzymatic activity. In vitro and in vivo data indicate that Eph-B forward signaling alters the methylation state of H3K4 by regulating 1C metabolism and locks neural stem cell in a differentiation-ready state. Our study highlights a functional link between cell-cell communication, metabolism, and epigenomic remodeling in the control of stem cell self-renewal.
Published: 2017

18. Chemotherapy-resistant human acute myeloid leukemia cells are not enriched for leukemic stem cells but require oxidative metabolism

Author: François Vergez, Marine Fraisse, Nicolas Broin, Thomas Farge, Robin L. Perry, Jean-Emmanuel Sarry, Audrey Sarry, Suzanne Tavitian, Stéphanie Cassant-Sourdy, Mayumi Sugita, Laetitia K. Linares, Jason S. Iacovoni, Claudie Bosc, Olivier Duchamp, Gwenn Danet-Desnoyers, Fabienne De Toni, Sarah J. Scotland, Y Barreira, Pierre Hirsch, Emmanuel Griessinger, Estelle Saland, Camille Montersino, Rémy Castellano, Héléna Boutzen, Nizar Serhan, Laurent Vallar, Martin Carroll, Christian Recher, Moshen Hosseini, Yves Collette, Lara Gales, François Delhommeau, Marion David, Marie-Laure Nicolau-Travers, Jean-Charles Portais, Nesrine Aroua, Lucille Stuani, Clément Larrue, Tony Kaoma, Tony Lionel Palama, Mary A. Selak, Barbara Garmy-Susini, Virginie Féliu, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Oncology, University Hospital-Hälsouniversitetet Universitetssjukhuset, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), U1065 Centre Méditerranéen de Médecine Moléculaire, Université de Nice Sophia-Antipolis (UNSA), Oncodesign, UMS006 Service d'Experimentation Animale, Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S938 CDR Saint-Antoine, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées, Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation ARC [SFI20121205478], Laboratoire d'Excellence Toulouse Cancer (TOUCAN) [ANR11-LABEX], Programme Hospitalo-Universitaire en Cancerologie (CAPTOR) [ANR11-PHUC0001], INCA [PLBIO 2012-105], Veterans Affairs Administration [1I01BX000918-01], NIH [1R01CA149566-01A1], Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31] (LMPM), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe 11-E.Moyal/C.Toulas, Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie clinique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CRLCC Henri Becquerel-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Luxembourg Institute of Health (LIH), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncodesign Inc., Oncodesign Biotechnology®, Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre Européen de Résonance Magnétique Nucléaire à Très Hauts Champs (CERMNTHC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Service d'immunologie et hématologies biologiques [Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Sorbonne Université (SU)-CHU Saint-Antoine [APHP], Service d'hématologie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncodesign [Dijon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Linares, Laetitia, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: CD36 Antigens, 0301 basic medicine, Myeloid, cancerologie, Mitochondrion, human health, Oxidative Phosphorylation, Mice, pharmacotherapy, 0302 clinical medicine, protéine mitochondriale, chimiothérapie, leucemie, Cytarabine, leukemia, Myeloid leukemia, santé humaine, Mitochondria, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, Biochemistry, 030220 oncology & carcinogenesis, oncologie, oncology, Neoplastic Stem Cells, Stem cell, medicine.drug, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Downregulation and upregulation, Cell Line, Tumor, medicine, Animals, Humans, Cell Lineage, chimiothérapie, oncologie, cancerologie, approche thérapeutique, leucemie, protéine mitochondriale, santé humaine, approche thérapeutique, medicine.disease, Xenograft Model Antitumor Assays, carbohydrates (lipids), 030104 developmental biology, Drug Resistance, Neoplasm, Cell culture, Cancer research, pharmacotherapy, oncology, leukemia, human health, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSC). To validate this hypothesis in vivo, we developed a clinically relevant chemotherapeutic approach treating patient-derived xenografts (PDX) with cytarabine (AraC). AraC residual AML cells are enriched in neither immature, quiescent cells nor LSCs. Strikingly, AraC-resistant preexisting and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. AraC residual cells exhibited increased fatty-acid oxidation, upregulated CD36 expression, and a high OXPHOS gene signature predictive for treatment response in PDX and patients with AML. High OXPHOS but not low OXPHOS human AML cell lines were chemoresistant in vivo. Targeting mitochondrial protein synthesis, electron transfer, or fatty-acid oxidation induced an energetic shift toward low OXPHOS and markedly enhanced antileukemic effects of AraC. Together, this study demonstrates that essential mitochondrial functions contribute to AraC resistance in AML and are a robust hallmark of AraC sensitivity and a promising therapeutic avenue to treat AML residual disease. Significance: AraC-resistant AML cells exhibit metabolic features and gene signatures consistent with a high OXPHOS status. In these cells, targeting mitochondrial metabolism through the CD36–FAO–OXPHOS axis induces an energetic shift toward low OXPHOS and strongly enhanced antileukemic effects of AraC, offering a promising avenue to design new therapeutic strategies and fight AraC resistance in AML. Cancer Discov; 7(7); 716–35. ©2017 AACR. See related commentary by Schimmer, p. 670. This article is highlighted in the In This Issue feature, p. 653
Published: 2017
Full Text: View/download PDF

19. Molecular Biomarkers for Weight Control in Obese Individuals Subjected to a Multiphase Dietary Intervention

Author: Arne Astrup, Jérôme Carayol, Armand Valsesia, Nathalie Villa-Vialaneix, Marie-Adeline Marques, Dominique Langin, Sophie Bonnel, Lucile Mir, Jennifer Bolton, Jason S. Iacovoni, Nathalie Viguerie, Emilie Montastier, Wim H. M. Saris, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRA), Institut National de la Recherche Agronomique (INRA), RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, RS: NUTRIM - HB/BW section A, and RS: NUTRIM - R1 - Metabolic Syndrome
Subjects: 0301 basic medicine, Male, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, IGFBP3, Adipose tissue, Biochemistry, 0302 clinical medicine, Endocrinology, Weight loss, Weight management, Gene Regulatory Networks, Osteonectin, MACROPHAGES, 2. Zero hunger, BINDING PROTEIN-3, Extracellular Matrix Proteins, ADIPOCYTE DIFFERENTIATION, Membrane Glycoproteins, WOMEN, TGF-BETA, Middle Aged, Real-time polymerase chain reaction, ADIPOSE-TISSUE, SKELETAL-MUSCLE, Female, Ubiquitin-Specific Proteases, medicine.symptom, RESTRICTION, Adult, medicine.medical_specialty, Follistatin-Related Proteins, Calorie restriction, Quantitative Trait Loci, Subcutaneous Fat, Down-Regulation, 030209 endocrinology & metabolism, Context (language use), Enzyme-Linked Immunosorbent Assay, Biology, Real-Time Polymerase Chain Reaction, Transforming Growth Factor beta1, 03 medical and health sciences, Internal medicine, TISSUE GENE-EXPRESSION, medicine, Humans, Obesity, RNA, Messenger, Caloric Restriction, Polymorphism, Genetic, Gene Expression Profiling, Biochemistry (medical), Calcium-Binding Proteins, Membrane Proteins, alpha-Crystallin B Chain, Microarray Analysis, 030104 developmental biology, Insulin-Like Growth Factor Binding Protein 3, FAT, Expression quantitative trait loci, Cell Adhesion Molecules, Biomarkers
Abstract: Context Although calorie restriction has proven beneficial for weight loss, long-term weight control is variable between individuals. Objective To identify biomarkers of successful weight control during a dietary intervention (DI). Design, Setting, and Participants Adipose tissue (AT) transcriptomes were compared between 21 obese individuals who either maintained weight loss or regained weight during the DI. Results were validated on 310 individuals from the same study using quantitative reverse transcription polymerase chain reaction and protein levels of potential circulating biomarkers measured by enzyme-linked immunosorbent assay. Intervention Individuals underwent 8 weeks of low-calorie diet, then 6 months of ad libitum diet. Outcome Measure Weight changes at the end of the DI. Results We evaluated six genes that had altered expression during DI, encode secreted proteins, and have not previously been implicated in weight control (EGFL6, FSTL3, CRYAB, TNMD, SPARC, IGFBP3), as well as genes for which baseline expression differed between those with good and poor weight control (ASPN, USP53). Changes in plasma concentrations of EGFL6, FSTL3, and CRYAB mirrored AT messenger RNA expression; all decreased during DI in individuals with good weight control. ASPN and USP53 had higher baseline expression in individuals who went on to have good weight control. Expression quantitative trait loci analysis found polymorphisms associated with expression levels of USP53 in AT. A regulatory network was identified in which transforming growth factor β1 (TGF-β1) was responsible for downregulation of certain genes during DI in good controllers. Interestingly, ASPN is a TGF-β1 inhibitor. Conclusions We found circulating biomarkers associated with weight control that could influence weight management strategies and genes that may be prognostic for successful weight control.
Published: 2016
Full Text: View/download PDF

20. HuR-dependent loading of miRNA RISC to the mRNA encoding the Ras-related small GTPase RhoB controls its translation during UV-induced apoptosis

Author: G Maillot, Jason S. Iacovoni, Gilles Favre, S Polès, V Glorian, and Stéphan Vagner
Subjects: Ultraviolet Rays, RHOB, Apoptosis, Biology, Cell Line, Luciferases, Firefly, RNA interference, microRNA, RhoB GTP-Binding Protein, Humans, Small GTPase, RNA, Messenger, RNA, Small Interfering, rhoB GTP-Binding Protein, 3' Untranslated Regions, Molecular Biology, Original Paper, Messenger RNA, Binding Sites, Three prime untranslated region, Translation (biology), Cell Biology, MicroRNAs, ELAV Proteins, Cancer research, RNA Interference, Protein Binding
Abstract: Of critical importance in the stress response is the post-transcriptional control of the expression of important genes involved in the control of cell survival and apoptosis. Here we report that miR-19, an oncogenic component of the miR-17-92/Oncomir-1 microRNA polycistron, regulates the expression of Ras homolog B (RhoB) in keratinocytes upon exposure to ultraviolet (UV) radiation. Strikingly, we could not find any evidence for deregulated expression of miR-19 during UV treatment. However, we show that miR-19-mediated regulation of antiapoptotic RhoB expression requires the binding of human antigen R (HuR), an AU-rich element binding protein, to the 3'-untranslated region of the rhoB mRNA. We propose that the loss of the interdependent binding between HuR and miR-19 to the rhoB mRNA upon UV exposure relieves this mRNA from miR-19-dependent inhibition of translation and contributes to the apoptotic response.
Published: 2011
Full Text: View/download PDF

21. Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

Author: Jacques Côté, Magdalena Skrzypczak, Bernard Fongang, Gaëlle Legube, Krzysztof Ginalski, François Aymard, Norbert Dojer, Vincent Rocher, Jason S. Iacovoni, Maga Rowicka, Thomas Clouaire, Anna Biernacka, Coline Arnould, Anahita Lashgari, Marion Aguirrebengoa, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), SIAAP - Direction du Développement et de la Prospective, SIAAP, Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, 02-089 Warsaw, Poland, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry and Molecular Biology, University of Texas Medical Branch at Galveston, Galveston, TX 77555 USA., Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, DNA Repair, [SDV]Life Sciences [q-bio], genetic processes, homologous recombination, Biology, DSB repair, histone H1, Article, non-homologous end joining, Genomic Instability, Histones, 03 medical and health sciences, chemistry.chemical_compound, Histone H1, Cell Line, Tumor, Histone H2B, DNA double-strand breaks, Humans, DNA Breaks, Double-Stranded, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, γH2AX, Molecular Biology, ComputingMilieux_MISCELLANEOUS, histone modifications, fungi, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, 53BP1, Chromatin, 3. Good health, Cell biology, ChIP-seq, Non-homologous end joining, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Histone, chemistry, biology.protein, Human genome, K562 Cells, Tumor Suppressor p53-Binding Protein 1, Homologous recombination, DNA
Abstract: Summary Double-strand breaks (DSBs) are extremely detrimental DNA lesions that can lead to cancer-driving mutations and translocations. Non-homologous end joining (NHEJ) and homologous recombination (HR) represent the two main repair pathways operating in the context of chromatin to ensure genome stability. Despite extensive efforts, our knowledge of DSB-induced chromatin still remains fragmented. Here, we describe the distribution of 20 chromatin features at multiple DSBs spread throughout the human genome using ChIP-seq. We provide the most comprehensive picture of the chromatin landscape set up at DSBs and identify NHEJ- and HR-specific chromatin events. This study revealed the existence of a DSB-induced monoubiquitination-to-acetylation switch on histone H2B lysine 120, likely mediated by the SAGA complex, as well as higher-order signaling at HR-repaired DSBs whereby histone H1 is evicted while ubiquitin and 53BP1 accumulate over the entire γH2AX domains., Graphical Abstract, Highlights • DSB-chromatin landscape and HR/NHEJ chromatin signatures uncovered by ChIP-seq • H2BK120 undergoes a switch from ubiquitination to acetylation at a local scale • H1 is removed and ubiquitin accumulates on entire γH2AX domains, mainly at HR DSB • 53BP1 spreads over megabase-sized domains, mostly in G1 at HR-prone DSBs, Using ChIP-seq in a cell line where multiple annotated DNA double-strand breaks can be induced on the human genome, Clouaire et al. report a comprehensive view of the chromatin landscape set up at DSBs and decipher the chromatin signature associated with HR and NHEJ repair.
Published: 2018
Full Text: View/download PDF

22. High-resolution profiling of γH2AX around DNA double strand breaks in the mammalian genome

Author: Didier Trouche, Jason S. Iacovoni, Imen Lassadi, Estelle Nicolas, Pierre Caron, Gaëlle Legube, Laurent Massip, Institut Fédératif de Recherche Bio-médicale Institution (IFR150), Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie moléculaire eucaryote (LBME), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Caron, Pierre, IFR150, Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Transcription, Genetic, [SDV]Life Sciences [q-bio], Restriction Mapping, RNA polymerase II, Genome, Article, General Biochemistry, Genetics and Molecular Biology, Cell Line, Histones, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Transcription (biology), Humans, DNA Breaks, Double-Stranded, Phosphorylation, Molecular Biology, Gene, 030304 developmental biology, Transcription bubble, Genetics, 0303 health sciences, General Immunology and Microbiology, biology, General Neuroscience, Chromosome Mapping, Chromatin, Cell biology, [SDV] Life Sciences [q-bio], Histone, chemistry, 030220 oncology & carcinogenesis, biology.protein, DNA
Abstract: International audience; Chromatin acts as a key regulator of DNA-related processes such as DNA damage repair. Although ChIP-chip is a powerful technique to provide high-resolution maps of protein-genome interactions, its use to study DNA double strand break (DSB) repair has been hindered by the limitations of the available damage induction methods. We have developed a human cell line that permits induction of multiple DSBs randomly distributed and unambiguously positioned within the genome. Using this system, we have generated the first genome-wide mapping of gammaH2AX around DSBs. We found that all DSBs trigger large gammaH2AX domains, which spread out from the DSB in a bidirectional, discontinuous and not necessarily symmetrical manner. The distribution of gammaH2AX within domains is influenced by gene transcription, as parallel mappings of RNA Polymerase II and strand-specific expression showed that gammaH2AX does not propagate on active genes. In addition, we showed that transcription is accurately maintained within gammaH2AX domains, indicating that mechanisms may exist to protect gene transcription from gammaH2AX spreading and from the chromatin rearrangements induced by DSBs.
Published: 2010
Full Text: View/download PDF

23. A physical and functional link between splicing factors promotes pre-mRNA 3′ end processing

Author: Stéphan Vagner, Stefania Millevoi, Jason S. Iacovoni, Clarisse Loulergue, Adrien Decorsière, Michael Antoniou, Sandra Bernat, Equipe 11-E.Moyal/C.Toulas, Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Claudius Regaud, King's College London School of Medicine, and Guy's Hospital [London]
Subjects: RNA Splicing Factors, Polyadenylation, [SDV]Life Sciences [q-bio], beta-Globins, Regulatory Sequences, Ribonucleic Acid, environment and public health, 03 medical and health sciences, Splicing factor, 0302 clinical medicine, RNA Precursors, Genetics, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Polypyrimidine tract-binding protein, 3' Untranslated Regions, Conserved Sequence, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Base Sequence, Heterogeneous-Nuclear Ribonucleoprotein Group F-H, biology, Three prime untranslated region, Alternative splicing, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Molecular biology, 030220 oncology & carcinogenesis, RNA splicing, biology.protein, RNA, RNA 3' End Processing, Poly A, Precursor mRNA, Polypyrimidine Tract-Binding Protein
Abstract: Polypyrimidine tract-binding protein (PTB) is a splicing regulator that also plays a positive role in pre-mRNA 3' end processing when bound upstream of the polyadenylation signal (pA signal). Here, we address the mechanism of PTB stimulatory function in mRNA 3' end formation. We identify PTB as the protein factor whose binding to the human beta-globin (HBB) 3' UTR is abrogated by a 3' end processing-inactivating mutation. We show that PTB promotes both in vitro 3' end cleavage and polyadenylation and recruits directly the splicing factor hnRNP H to G-rich sequences associated with several pA signals. Increased binding of hnRNP H results in stimulation of polyadenylation through a direct interaction with poly(A) polymerase. Therefore, our results provide evidence of a concerted regulation of pA signal recognition by splicing factors bound to auxiliary polyadenylation sequence elements.
Published: 2009
Full Text: View/download PDF

24. Transcription of the human uncoupling protein 3 gene is governed by a complex interplay between the promoter and intronic sequences

Author: L. Lichtenstein, Dominique Langin, Claire Tiraby, Amandine Girousse, Jason S. Iacovoni, Francesc Villarroya, Aline Mairal, Geneviève Tavernier, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Departament de Bioquimica i Biologia Molecular and Institut de Biomedicina (IBUB), Universitat de Barcelona (UB), CIBER Fisiopatologia de la Obesidad y Nutrición, Instituto de Salud Carlos III [Madrid] (ISC), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Transcription, Genetic, Endocrinology, Diabetes and Metabolism, Transgene, Mice, Transgenic, 030209 endocrinology & metabolism, Biology, Ion Channels, Mitochondrial Proteins, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Internal Medicine, medicine, Animals, Humans, Insulin, Uncoupling Protein 3, Uncoupling protein, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Muscle, Skeletal, Promoter Regions, Genetic, Gene, 030304 developmental biology, UCP3, Genetics, 0303 health sciences, Reporter gene, Skeletal muscle, Promoter, Introns, Cell biology, medicine.anatomical_structure, Diabetes Mellitus, Type 2, Regulatory sequence, Energy Metabolism
Abstract: International audience; AIMS/HYPOTHESIS: Uncoupling protein (UCP) 3 is an inner mitochondrial membrane transporter mainly produced in skeletal muscle in humans. UCP3 plays a role in fatty acid metabolism and energy homeostasis and modulates insulin sensitivity. In humans, UCP3 content is higher in fast-twitch glycolytic muscle than in slow-twitch oxidative muscle and is dysregulated in type 2 diabetes. Here, we studied the molecular mechanisms determining human UCP3 levels in skeletal muscle and their regulation by fasting in transgenic mice. METHODS: We produced a series of transgenic lines with constructs bearing different putative regulatory regions of the human UCP3 gene, including promoter and intron sequences. UCP3 mRNA and reporter gene expression and activity were measured in different skeletal muscles and tissues. RESULTS: The profile of expression and the response to fasting and thyroid hormone of human UCP3 mRNA in transgenic mice with 16 kb of the human UCP3 gene were similar to that of the endogenous human gene. Various parts of the UCP3 promoter did not confer expression in transgenic lines. Inclusion of intron 1 resulted in an expression profile in skeletal muscle that was identical to that of human UCP3 mRNA. Further dissection of intron 1 revealed that distinct regions were involved in skeletal muscle expression, distribution among fibre types and response to fasting. CONCLUSIONS/INTERPRETATION: The control of human UCP3 transcription in skeletal muscle is not solely conferred by the promoter, but depends on several cis-acting elements in intron 1, suggesting a complex interplay between the promoter and intronic sequences.
Published: 2009
Full Text: View/download PDF

25. Translational Induction of VEGF Internal Ribosome Entry Site Elements During the Early Response to Ischemic Stress

Author: Leonel Prado-Lourenco, Stéphanie Bornes, Amandine Bastide, Jason S. Iacovoni, Hervé Prats, Anne-Catherine Prats, Eric Lacazette, Christian Touriol, Catherine Zanibellato, Simon, Marie Francoise, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and MilleGen Prologue Biotech
Subjects: Male, Vascular Endothelial Growth Factor A, Physiology, Angiogenesis, MESH: Codon, Initiator, Response element, Codon, Initiator, MESH: Base Sequence, Mice, L Cells, Start codon, Ischemia, MESH: Reverse Transcriptase Polymerase Chain Reaction, Protein biosynthesis, MESH: Animals, MESH: Stress, Physiological, MESH: L Cells (Cell Line), MESH: Organ Specificity, MESH: Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, MESH: Hindlimb, MESH: Gene Expression Regulation, Hindlimb, Cell biology, Organ Specificity, MESH: Protein Biosynthesis, Acute Disease, MESH: 5' Untranslated Regions, MESH: Acute Disease, Cardiology and Cardiovascular Medicine, MESH: Neovascularization, Physiologic, MESH: Mice, Transgenic, Molecular Sequence Data, MESH: Sequence Alignment, Neovascularization, Physiologic, Mice, Transgenic, Biology, MESH: Sequence Homology, Nucleic Acid, Vasculogenesis, Species Specificity, Stress, Physiological, Sequence Homology, Nucleic Acid, Animals, Humans, MESH: Species Specificity, RNA, Messenger, Muscle, Skeletal, MESH: Mice, MESH: RNA, Messenger, Messenger RNA, Reporter gene, MESH: Molecular Sequence Data, MESH: Humans, Base Sequence, MESH: Vascular Endothelial Growth Factor A, MESH: Male, Internal ribosome entry site, Gene Expression Regulation, Protein Biosynthesis, Immunology, NIH 3T3 Cells, MESH: Ischemia, 5' Untranslated Regions, Sequence Alignment, MESH: NIH 3T3 Cells
Abstract: International audience; Vascular endothelial growth factor-A (VEGF), a powerful factor involved in vasculogenesis and angiogenesis, is translationally regulated through 2 independent internal ribosome entry sites (IRESs A and B). IRESs enable an mRNA to be translated under conditions in which 5'-cap-dependent translation is inhibited, such as low oxygen stress. In the VEGF mRNA, IRES A influences translation at the canonical AUG codon, whereas the 5' IRES B element regulates initiation at an upstream, in frame CUG. In this study, we have developed transgenic mice expressing reporter genes under the control of these 2 IRESs. We reveal that although these IRESs display low activity in embryos and adult tissues, they permit efficient translation at early time points in ischemic muscle, a stress under which cap-dependent translation is inhibited. These results demonstrate the in vivo efficacy of the VEGF IRESs in response to a local environmental stress such as hypoxia.
Published: 2007
Full Text: View/download PDF

26. Periodontal dysbiosis linked to periodontitis is associated with cardiometabolic adaptation to high-fat diet in mice

Author: Vincent Azalbert, F. Reichardt, Anaïs Giry, Pascale Loubieres, Vincent Blasco-Baque, Pauline Marck, Maxime Branchereau, Christophe Heymes, André Colom, François Tercé, Matteo Serino, Roshan Padmanabhan, Aurélie Waget, Jason S. Iacovoni, and Rémy Burcelin
Subjects: 0301 basic medicine, Male, Physiology, Streptococcaceae, Prevotella, Type 2 diabetes, Gut flora, Prevotellaceae, Diet, High-Fat, 03 medical and health sciences, Mice, 0302 clinical medicine, Physiology (medical), Glucose Intolerance, Plasminogen Activator Inhibitor 1, medicine, Animals, Ventricular Function, Microbiome, Periodontitis, Dental alveolus, Hepatology, biology, Tumor Necrosis Factor-alpha, Microbiota, Gastroenterology, 030206 dentistry, medicine.disease, biology.organism_classification, Dimethylallyltranstransferase, Adaptation, Physiological, Mice, Inbred C57BL, 030104 developmental biology, Glycemic index, Cardiovascular Diseases, Immunology, Dysbiosis
Abstract: Periodontitis and type 2 diabetes are connected pandemic diseases, and both are risk factors for cardiovascular complications. Nevertheless, the molecular factors relating these two chronic pathologies are poorly understood. We have shown that, in response to a long-term fat-enriched diet, mice present particular gut microbiota profiles related to three metabolic phenotypes: diabetic-resistant (DR), intermediate (Inter), and diabetic-sensitive (DS). Moreover, many studies suggest that a dysbiosis of periodontal microbiota could be associated with the incidence of metabolic and cardiac diseases. We investigated whether periodontitis together with the periodontal microbiota may also be associated with these different cardiometabolic phenotypes. We report that the severity of glucose intolerance is related to the severity of periodontitis and cardiac disorders. In detail, alveolar bone loss was more accentuated in DS than Inter, DR, and normal chow-fed mice. Molecular markers of periodontal inflammation, such as TNF-α and plasminogen activator inhibitor-1 mRNA levels, correlated positively with both alveolar bone loss and glycemic index. Furthermore, the periodontal microbiota of DR mice was dominated by the Streptococcaceae family of the phylum Firmicutes, whereas the periodontal microbiota of DS mice was characterized by increased Porphyromonadaceae and Prevotellaceae families. Moreover, in DS mice the periodontal microbiota was indicated by an abundance of the genera Prevotella and Tannerella, which are major periodontal pathogens. PICRUSt analysis of the periodontal microbiome highlighted that prenyltransferase pathways follow the cardiometabolic adaptation to a high-fat diet. Finally, DS mice displayed a worse cardiac phenotype, percentage of fractional shortening, heart rhythm, and left ventricle weight-to-tibia length ratio than Inter and DR mice. Together, our data show that periodontitis combined with particular periodontal microbiota and microbiome is associated with metabolic adaptation to a high-fat diet related to the severity of cardiometabolic alteration.
Published: 2015

27. hnRNP A1-mediated translational regulation of the G quadruplex-containing RON receptor tyrosine kinase mRNA linked to tumor progression

Author: Morgane Le Bras, Thomas Filleron, Magali Lacroix-Triki, Henri Roché, Gilles Favre, Stéphan Vagner, Sandra Pierredon, Stefania Millevoi, Marie-Paule Teulade-Fichou, Jason S. Iacovoni, and Anne Cammas
Subjects: 0301 basic medicine, Untranslated region, viruses, Heterogeneous Nuclear Ribonucleoprotein A1, RNA-binding protein, translation, Breast Neoplasms, Kaplan-Meier Estimate, environment and public health, Receptor tyrosine kinase, 03 medical and health sciences, 0302 clinical medicine, breast cancer, Translational regulation, Protein biosynthesis, Medicine, Humans, metastasis, RNA, Messenger, Messenger RNA, biology, business.industry, Receptor Protein-Tyrosine Kinases, RON, Cell biology, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, Tumor progression, 030220 oncology & carcinogenesis, Protein Biosynthesis, biology.protein, Disease Progression, Female, business, Research Paper
Abstract: The expression and role of RNA binding proteins (RBPs) controlling mRNA translation during tumor progression remains largely uncharacterized. Analysis by immunohistochemistry of the expression of hnRNP A1, hnRNPH, RBM9/FOX2, SRSF1/ASF/SF2, SRSF2/SC35, SRSF3/SRp20, SRSF7/9G8 in breast tumors shows that the expression of hnRNP A1, but not the other tested RBPs, is associated with metastatic relapse. Strikingly, hnRNP A1, a nuclear splicing regulator, is also present in the cytoplasm of tumor cells of a subset of patients displaying exceedingly worse prognosis. Expression of a cytoplasmic mutant of hnRNP A1 leads to increased translation of the mRNA encoding the tyrosine kinase receptor RON/MTS1R, known for its function in tumor dissemination, and increases cell migration in vitro. hnRNP A1 directly binds to the 5' untranslated region of the RON mRNA and activates its translation through G-quadruplex RNA secondary structures. The correlation between hnRNP A1 and RON tumoral expression suggests that these findings hold clinical relevance.
Published: 2015

28. The Gut Microbiota Regulates Intestinal CD4 T Cells Expressing RORγt and Controls Metabolic Disease

Author: Florence Servant, Philippe Valet, Jacques Amar, Matteo Serino, Julie Charpentier, Meryem Aloulou, Nicolas Fazilleau, Anaïs Giry, Michael Courtney, Gérard Eberl, Céline Pomié, Rémy Burcelin, Benjamin Lelouvier, Pascale Klopp, Xavier Collet, Lotta Stenman, Sampo J. Lahtinen, Victorine Douin-Echinard, Christophe Heymes, Cédric Dray, Aurélie Waget, Jason S. Iacovoni, Lucile Garidou, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Embryology and Histopathology, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), DuPont Health & Nutrition, Vaiomer, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut LITEN - Laboratoire des Matériaux Avancés (LITEN-LMA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute of Biochemistry, University of Lausanne and ISREC, Epalinges, Switzerland., Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Fazilleau, Nicolas
Subjects: CD4-Positive T-Lymphocytes, Male, Adoptive cell transfer, Physiology, [SDV]Life Sciences [q-bio], Ileum, Gut flora, Diet, High-Fat, digestive system, Interleukin 22, Mice, 03 medical and health sciences, 0302 clinical medicine, RAR-related orphan receptor gamma, medicine, Animals, Obesity, Molecular Biology, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Lamina propria, biology, Interleukin-17, Immunity, Cell Biology, Nuclear Receptor Subfamily 1, Group F, Member 3, biology.organism_classification, Small intestine, Gastrointestinal Microbiome, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Diabetes Mellitus, Type 2, Gene Expression Regulation, 030220 oncology & carcinogenesis, CD4 Antigens, Immunology, Th17 Cells, Gene Deletion, Homeostasis
Abstract: SummaryA high-fat diet (HFD) induces metabolic disease and low-grade metabolic inflammation in response to changes in the intestinal microbiota through as-yet-unknown mechanisms. Here, we show that a HFD-derived ileum microbiota is responsible for a decrease in Th17 cells of the lamina propria in axenic colonized mice. The HFD also changed the expression profiles of intestinal antigen-presenting cells and their ability to generate Th17 cells in vitro. Consistent with these data, the metabolic phenotype was mimicked in RORγt-deficient mice, which lack IL17 and IL22 function, and in the adoptive transfer experiment of T cells from RORγt-deficient mice into Rag1-deficient mice. We conclude that the microbiota of the ileum regulates Th17 cell homeostasis in the small intestine and determines the outcome of metabolic disease.
Published: 2015
Full Text: View/download PDF

29. Specific Macrophage Subtypes Influence the Progression of Rhabdomyolysis-Induced Kidney Injury

Author: Frédéric Martins, Céline Guilbeau-Frugier, Joost P. Schanstra, Bénédicte Buffin-Meyer, Jason S. Iacovoni, Jean-Loup Bascands, Bernard Pipy, Dominique Chauveau, Alexia Zakaroff-Girard, Audrey Casemayou, Laure Ducasse, Julie Belliere, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CHU Toulouse [Toulouse], Génome et Transcriptome - Plateforme Génomique ( GeT-PlaGe), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Plateforme Bioinformatique, Laboratoire des interactions plantes micro-organismes (LIPM), Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Institut de Recherche pour le Développement (IRD), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: Glycerol, Male, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Sensitivity and Specificity, acute renal failure, Proinflammatory cytokine, 03 medical and health sciences, Mice, Random Allocation, 0302 clinical medicine, Fibrosis, Risk Factors, medicine, Animals, Humans, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Kidney, Immunology and pathology, biology, business.industry, Myoglobin, fibrosis, Acute kidney injury, General Medicine, Acute Kidney Injury, medicine.disease, Flow Cytometry, 3. Good health, macrophages, Disease Models, Animal, medicine.anatomical_structure, Basic Research, Integrin alpha M, Nephrology, biology.protein, Disease Progression, rhabdomyolysis, Clodronic acid, Clodronic Acid, business, Infiltration (medical), Rhabdomyolysis, chronic kidney disease, medicine.drug
Abstract: International audience; Rhabdomyolysis can be life threatening if complicated by AKI. Macrophage infiltration has been observed in rat kidneys after glycerol-induced rhabdomyolysis, but the role of macrophages in rhabdomyolysis-induced AKI remains unknown. Here, in a patient diagnosed with rhabdomyolysis, we detected substantial macrophage infiltration in the kidney. In a mouse model of rhabdomyolysis-induced AKI, diverse renal macrophage phenotypes were observed depending on the stage of the disease. Two days after rhabdomyolysis, F4/80(low)CD11b(high)Ly6b(high)CD206(low) kidney macrophages were dominant, whereas by day 8, F4/80(high)CD11b(+)Ly6b(low)CD206(high) cells became the most abundant. Single-cell gene expression analyses of FACS-sorted macrophages revealed that these subpopulations were heterogeneous and that individual cells simultaneously expressed both M1 and M2 markers. Liposomal clodronate-mediated macrophage depletion significantly reduced the early infiltration of F4/80(low)CD11b(high)Ly6b(high)CD206(low) macrophages. Furthermore, transcriptionally regulated targets potentially involved in disease progression, including fibronectin, collagen III, and chemoattractants that were identified via single-cell analysis, were verified as macrophage-dependent in situ. In vitro, myoglobin treatment induced proximal tubular cells to secrete chemoattractants and macrophages to express proinflammatory markers. At day 30, liposomal clodronate-mediated macrophage depletion reduced fibrosis and improved both kidney repair and mouse survival. Seven months after rhabdomyolysis, histologic lesions were still present but were substantially reduced with prior depletion of macrophages. These results suggest an important role for macrophages in rhabdomyolysis-induced AKI progression and advocate the utility of long-term follow-up for patients with this disease.
Published: 2015
Full Text: View/download PDF

30. Non-redundant Functions of ATM and DNA-PKcs in Response to DNA Double-Strand Breaks

Author: Pierre Caron, Jonathan Choudjaye, Thomas Clouaire, Béatrix Bugler, Virginie Daburon, Marion Aguirrebengoa, Thomas Mangeat, Jason S. Iacovoni, Alejandro Álvarez-Quilón, Felipe Cortés-Ledesma, Gaëlle Legube
Published: 2015
Full Text: View/download PDF

31. v-Jun targets showing an expression pattern that correlates with the transformed cellular phenotype

Author: Jason S. Iacovoni, Peter K. Vogt, Steven B Cohen, and Thorsten Berg
Subjects: Cancer Research, Tumor suppressor gene, Proto-Oncogene Proteins c-jun, Protein Array Analysis, Biology, medicine.disease_cause, Molecular biology, Phenotype, Up-Regulation, Mice, Cell Transformation, Neoplastic, Cell culture, Gene expression, Genetics, medicine, Animals, MARCKS, Carcinogenesis, Molecular Biology, Gene, Transcription factor, Oligonucleotide Array Sequence Analysis
Abstract: Targets of the oncogenic transcription factor v-Jun in the murine cell line C3H 10T1/2 cells have been identified using DNA microarrays. Two targets, Akap12 and Marcks, are downregulated in transformed cells and are known tumor suppressor genes. Overexpression of either Akap12 or Marcks in v-Jun-transformed cells reverses the transformed phenotype and leads to the re-expression of the other tumor suppressor gene, suggesting that these two genes cooperate in the establishment of the nontransformed state. Reverted cells continue to express v-Jun at high levels and also re-express c-Jun, which is normally repressed by v-Jun. A panel of six cell lines has been generated to evaluate the expression levels of other v-Jun targets in 10T1/2 cells. With these cells, we find that the upregulated target Sprr1a has an expression pattern that correlates with the transformed phenotype.
Published: 2004
Full Text: View/download PDF

32. Deciphering the chromatin landscape induced around DNA double strand breaks

Author: Laurent Massip, Jason S. Iacovoni, Gaëlle Legube, Didier Trouche, Pierre Caron, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Chromatin Immunoprecipitation, Microarray, Immunoprecipitation, [SDV]Life Sciences [q-bio], genetic processes, Fluorescent Antibody Technique, Biology, Genome, Histones, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cell Line, Tumor, Humans, DNA Breaks, Double-Stranded, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Base Sequence, Genome, Human, Cell Cycle, Nuclear Proteins, Cell Biology, Molecular biology, Chromatin, Cell biology, Tamoxifen, Restriction enzyme, chemistry, Cell culture, 030220 oncology & carcinogenesis, Chromatin immunoprecipitation, DNA, Developmental Biology
Abstract: DNA double strand breaks (DSBs) are among the most deleterious forms of lesions and deciphering the details of the chromatin landscape induced around DSBs represents a great challenge for molecular biologists. Chromatin Immunoprecipitation, followed by microarray hybridisation (ChIP-chip) or high-throughput sequencing (ChIP-seq), are powerful techniques that provide high-resolution maps of protein-genome interactions. However, applying these techniques to study chromatin changes induced around DSBs was previously hindered due to a lack of suitable DSB induction techniques. We have recently developed an experimental system utilizing a restriction enzyme fused to a modified oestrogen receptor ligand binding domain (AsiSI-ER), which generates multiple, sequence-specific and unambiguously positioned DSBs across the genome upon induction with 4-hydroxytamoxifen (4OHT).(1) Cell lines expressing this construct represent a powerful tool to study specific chromatin changes during DSB repair, enabling high-resolution profiling of DNA repair complexes and chromatin modifications induced around DSBs. Using this system, we have recently produced the first map of gammaH2AX, a DSB-induced chromatin modification, on two human chromosomes and have investigated its spreading properties.(1) Here we provide additional data characterizing the cell lines, present a genome-wide profile of gammaH2AX obtained by ChIP-seq, and discuss the potential of our system towards investigations of previously uncharacterized aspects of DSB repair.
Published: 2014
Full Text: View/download PDF

33. Human white and brite adipogenesis is supported by MSCA1 and is impaired by immune cells

Author: Anne Bouloumié, Jason S. Iacovoni, Benjamin Castel, Muriel Coupaye, Frédérique Gaits-Iacovoni, Fanny Volat, Nathalie Boulet, Pauline Decaunes, Séverine Ledoux, A. Remaury, Chloé Belles, Christophe Heymes, Pascual Ferrara, David Estève, Max Lafontan, Jean Galitzky, and Alexia Zakaroff-Girard
Subjects: Adult, medicine.medical_specialty, Population, Adipocytes, White, Adipose tissue, Inflammation, Biology, chemistry.chemical_compound, Adipocyte, Internal medicine, medicine, Humans, Progenitor cell, education, Cells, Cultured, Aged, education.field_of_study, Immunity, Cellular, Adipogenesis, Cell Biology, Middle Aged, Bone morphogenetic protein 7, Endocrinology, chemistry, Antigens, Surface, Molecular Medicine, Female, medicine.symptom, Stem cell, Developmental Biology
Abstract: Obesity-associated inflammation contributes to the development of metabolic diseases. Although brite adipocytes have been shown to ameliorate metabolic parameters in rodents, their origin and differentiation remain to be characterized in humans. Native CD45−/CD34+/CD31− cells have been previously described as human adipocyte progenitors. Using two additional cell surface markers, MSCA1 (tissue nonspecific alkaline phosphatase) and CD271 (nerve growth factor receptor), we are able to partition the CD45−/CD34+/CD31− cell population into three subsets. We establish serum-free culture conditions without cell expansion to promote either white/brite adipogenesis using rosiglitazone, or bone morphogenetic protein 7 (BMP7), or specifically brite adipogenesis using 3-isobuthyl-1-methylxanthine. We demonstrate that adipogenesis leads to an increase of MSCA1 activity, expression of white/brite adipocyte-related genes, and mitochondriogenesis. Using pharmacological inhibition and gene silencing approaches, we show that MSCA1 activity is required for triglyceride accumulation and for the expression of white/brite-related genes in human cells. Moreover, native immunoselected MSCA1+ cells exhibit brite precursor characteristics and the highest adipogenic potential of the three progenitor subsets. Finally, we provided evidence that MSCA1+ white/brite precursors accumulate with obesity in subcutaneous adipose tissue (sAT), and that local BMP7 and inflammation regulate brite adipogenesis by modulating MSCA1 in human sAT. The accumulation of MSCA1+ white/brite precursors in sAT with obesity may reveal a blockade of their differentiation by immune cells, suggesting that local inflammation contributes to metabolic disorders through impairment of white/brite adipogenesis. Stem Cells 2015;33:1277–1291
Published: 2014

34. Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks

Author: Sébastien Briois, François Aymard, Emmanuelle Guillou, Stephen P. Jackson, Gaëlle Legube, Christine K. Schmidt, Jason S. Iacovoni, Béatrix Bugler, Virginie Daburon, Pierre Caron, Kyle M. Miller, Caron, Pierre, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Cambridge [UK] (CAM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: DNA End-Joining Repair, DNA Repair, Transcription, Genetic, DNA repair, [SDV]Life Sciences [q-bio], DSB repair, NHEJ, HR, chromatin, transcription, ChIP-seq, H3K36me3, genetic processes, RAD51, Biology, Article, Cell Line, Homology directed repair, Histones, Structural Biology, Humans, DNA Breaks, Double-Stranded, Homologous Recombination, Molecular Biology, Transcriptionally active chromatin, Manchester Cancer Research Centre, ResearchInstitutes_Networks_Beacons/mcrc, fungi, DNA repair protein XRCC4, Molecular biology, Chromatin, Neoplasm Proteins, Non-homologous end joining, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], enzymes and coenzymes (carbohydrates), health occupations, Rad51 Recombinase, biological phenomena, cell phenomena, and immunity
Abstract: While both Homologous recombination (HR) and Non Homologous End Joining (NHEJ) can repair DNA double Strand Breaks (DSB), the mechanisms by which one or other of these pathways is chosen remain unclear. Here we show that transcriptionally active chromatin is preferentially repaired by HR. Using chromatin immunoprecipitation-sequencing (ChIP-seq), to analyse repair of multiple DSBs induced throughout the human genome, we identify an “HR- prone” subset of DSBs that recruit the HR protein RAD51, undergo resection and rely on RAD51 for efficient repair. These DSBs are located in actively transcribed genes, and targeted to HR repair via the transcription-elongation associated histone mark, histone H3 lysine 36 trimethylation (H3K36me3). In agreement, depletion of SETD2, the main H3K36 tri- methyltransferase, severely impedes HR at such DSBs. Our study thereby demonstrates a primary role of the chromatin context, in which a break occurs, in DSB repair.
Published: 2014
Full Text: View/download PDF

35. The DF-1 Chicken Fibroblast Cell Line: Transformation Induced by Diverse Oncogenes and Cell Death Resulting from Infection by Avian Leukosis Viruses

Author: Peter K. Vogt, Douglas N. Foster, Ivan Bottoli, Martin Himly, and Jason S. Iacovoni
Subjects: Programmed cell death, animal structures, Avian Leukosis Virus, Cell Death, Endogeny, Embryo, Chick Embryo, Oncogenes, Fibroblasts, Biology, Virus Replication, Virology, Fibroblast cell line, Cell Line, Transformation (genetics), Cell Transformation, Neoplastic, Cell killing, Genes, jun, Avian leukosis viruses, Cell culture, Animals, Chickens, Cells, Cultured
Abstract: DF-1 is a continuous cell line of chicken embryo fibroblasts. The cells are free of endogenous sequences related to avian sarcoma and leukosis viruses and have normal fibroblastic morphology. DF-1 cells support the replication of avian retroviruses; diverse oncogenes induce foci of oncogenic transformation on monolayers of DF-1, and avian leukosis viruses of envelope subgroups B, D, and C induce cell death and form plaques. The new cell line will greatly facilitate studies on oncogenic transformation and cell killing by avian viruses.
Published: 1998
Full Text: View/download PDF

36. Glutaredoxin is a direct target of oncogenic jun

Author: Peter K. Vogt, Jason S. Iacovoni, Martin E. Goller, and Ulrich Kruse
Subjects: Genetics, Cancer Research, Messenger RNA, Oncogene Protein p65(gag-jun), Proteins, Chick Embryo, Biology, Molecular biology, Homology (biology), GAP-43 Protein, Gene Expression Regulation, Downregulation and upregulation, Cell culture, Glutaredoxin, Gene expression, Protein biosynthesis, Animals, Oxidoreductases, Molecular Biology, Gene, Glutaredoxins
Abstract: We have analysed differential gene expression in v-jun-transformed chicken embryo fibroblasts (CEF) compared to normal CEF by using the directional tag PCR subtraction method. From a first generation of putative Jun targets four clones were selected for study; they are upregulated in jun-transformed cells. Three of these clones showed homology to known genes: glutaredoxin, growth associated protein (GAP)-43/neuromodulin, and phenobarbital-induced cytochrome P450. The expression of these genes was analysed in fibroblasts transformed by various oncogenes. Expression of the glutaredoxin mRNA could be induced by a Jun-estrogen receptor chimaera in the absence of de novo protein biosynthesis. Based on this observation we conclude that glutaredoxin is a direct target of v-Jun.
Published: 1998
Full Text: View/download PDF

37. Avian winged helix proteins CWH-1, CWH-2 and CWH-3 repress transcription from Qin binding sites

Author: Peter K. Vogt, Jason S. Iacovoni, Markus P. Freyaldenhoven, and Bettina S Freyaldenhoven
Subjects: Genetics, Cancer Research, Binding Sites, animal structures, Repressor, DNA, Winged Helix, Biology, DNA-binding protein, Avian Proteins, DNA-Binding Proteins, Repressor Proteins, DNA binding site, Transcription (biology), Transcriptional regulation, Binding site, Molecular Biology, Transcription factor, Transcription Factors
Abstract: The chicken winged helix proteins, CWH-1, CWH-2 and CWH-3, were isolated and identified by homology cloning using the winged helix sequence of the retroviral oncogene qin as a probe. The CWH proteins act as growth stimulators in chicken embryo fibroblasts and in this activity resemble the Qin protein. Qin is a transcriptional regulator that functions as a repressor, and its oncogenic potential is correlated with the ability to repress transcription. In this communication we show that CWH proteins are localized in the cell nucleus, recognize the Qin DNA binding site and also function as transcriptional repressors. The repression activity of CWH-3 was mapped to the region of amino acids 211 to 311, a domain that is homologous to the major repression domain of Qin.
Published: 1997
Full Text: View/download PDF

38. Determinants of human adipose tissue gene expression: impact of diet, sex, metabolic status, and cis genetic regulation

Author: Balbine Roussel, Hubert Vidal, Karine Clément, Dominique Langin, Arne Astrup, Nathalie Viguerie, Jason S. Iacovoni, Claus Holst, Marion Combes, Nathalie Villa-Vialaneix, Jörg Hager, Carine Valle, J. Alfredo Martínez, Emilie Montastier, Jean-José Maoret, Wim H. M. Saris, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Statistique, Analyse et Modélisation Multidisciplinaire (SAmos-Marin Mersenne) (SAMM), Université Paris 1 Panthéon-Sorbonne (UP1), Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Institute of Preventive Medicine, Copenhagen University Hospitals, Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de nutrition [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Franco-czech Laboratory for clinical research on obesity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Charles University [Prague] (CU), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], European Communities [DiOGenes FP6-513946, MoIPAGE LSHG-CT-2004-512066, ADAPT HEALTH-F2-2008-2011 00], Fondation pour la Recherche Medicale ANR LIPOB and OBELIP, Region Midi-Pyrenees, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Charles University [Prague] (CU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Vialaneix, Nathalie, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Institut des Maladies Métaboliques et Cardiovasculaires ( I2MC ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Statistique, Analyse et Modélisation Multidisciplinaire (SAmos-Marin Mersenne) ( SAMM ), Université Panthéon-Sorbonne ( UP1 ), Universidad de Navarra [Pamplona] ( UNAV ), Faculty of Life Sciences-University of Copenhagen ( KU ), Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Genomics Institute, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Panthéon-Sorbonne (UP1), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Charles University [Prague]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Cancer Research, Adipose tissue, Gene Expression, [SDV.GEN] Life Sciences [q-bio]/Genetics, Body Mass Index, 0302 clinical medicine, Weight loss, Gene expression, Molecular Cell Biology, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), 2. Zero hunger, Regulation of gene expression, Gene expression regulation, Metabolic Syndrome, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Genomics, [ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Santé publique et épidémiologie, obésité, Adipose Tissue, Medicine, Female, medicine.symptom, Research Article, medicine.medical_specialty, lcsh:QH426-470, Calorie restriction, Médecine humaine et pathologie, 030209 endocrinology & metabolism, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Sex Factors, Internal medicine, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Weight Loss, medicine, Genetics, Genome-Wide Association Studies, Humans, Obesity, Molecular Biology, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Nutrition, Caloric Restriction, Regulatory Networks, [SDV.GEN]Life Sciences [q-bio]/Genetics, Lipogenesis, Computational Biology, Human Genetics, medicine.disease, lcsh:Genetics, Endocrinology, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Human health and pathology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Metabolic syndrome, Genome Expression Analysis, Energy Intake, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Body mass index, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Weight control diets favorably affect parameters of the metabolic syndrome and delay the onset of diabetic complications. The adaptations occurring in adipose tissue (AT) are likely to have a profound impact on the whole body response as AT is a key target of dietary intervention. Identification of environmental and individual factors controlling AT adaptation is therefore essential. Here, expression of 271 transcripts, selected for regulation according to obesity and weight changes, was determined in 515 individuals before, after 8-week low-calorie diet-induced weight loss, and after 26-week ad libitum weight maintenance diets. For 175 genes, opposite regulation was observed during calorie restriction and weight maintenance phases, independently of variations in body weight. Metabolism and immunity genes showed inverse profiles. During the dietary intervention, network-based analyses revealed strong interconnection between expression of genes involved in de novo lipogenesis and components of the metabolic syndrome. Sex had a marked influence on AT expression of 88 transcripts, which persisted during the entire dietary intervention and after control for fat mass. In women, the influence of body mass index on expression of a subset of genes persisted during the dietary intervention. Twenty-two genes revealed a metabolic syndrome signature common to men and women. Genetic control of AT gene expression by cis signals was observed for 46 genes. Dietary intervention, sex, and cis genetic variants independently controlled AT gene expression. These analyses help understanding the relative importance of environmental and individual factors that control the expression of human AT genes and therefore may foster strategies aimed at improving AT function in metabolic diseases., Author Summary In obesity, an excess of adipose tissue is associated with dyslipidemia and diabetic complications. Gene expression is under the control of various genetic and environmental factors. As a central organ for the control of metabolic disturbances in conditions of both weight gain and loss, a comprehensive understanding of the control of adipose tissue gene expression is of paramount interest. We analyzed adipose tissue gene expression in obese individuals from the DiOGenes protocol, one of the largest dietary interventions worldwide. We found evidence for composite control of adipose tissue gene expression by nutrition, metabolic syndrome, body mass index, sex, and genotype with two main novel features. First, we observed a preeminent effect of sex on adipose tissue gene expression, which was independent of nutritional status, fat mass, and sex chromosomes. Second, the control of gene expression by cis genetic factors was unaffected by sex and nutritional status. Altogether, the effects of the investigated factors were most often independent of each other. Comprehension of the relative importance of environmental and individual factors that control the expression of human adipose tissue genes may help deciphering strategies aimed at controlling adipose tissue function during metabolic disorders.
Published: 2012
Full Text: View/download PDF

39. Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota

Author: Claire Cenac, Pierre Monsan, Aurélie Waget, Pascale Klopp, Philippe Valet, Jacques Amar, Jason S. Iacovoni, Jérôme Mariette, Rémy Burcelin, Mathieu Bergé, Jérôme Lluch, Audrey Baylac, Anne Bouloumié, Sandra Grès, Christophe Klopp, Françoise Ouarné, Christine Roques, Olivier Bouchez, Vassilia Theodorou, Matteo Serino, Elodie Luche, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Adhésion Bacterienne et Formation de Biofilms, PRES Université de Toulouse, ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Plateforme Bio-informatique Toulouse Genopole®, UBIA INRA, Toulouse Genopole, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), CRITT Bio-Industrie, Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Service de Médecine Interne et Hypertension Artérielle [Toulouse], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], his work was supported by grants from Agence Nationale pour la Recherche (ANR) to RB and collaborators (ANR-Florinflam and Transflora), in part, by the European Commission's Seventh Framework programme under grant agreement No 241913 (FLORINASH) to RB and by the Benjamin Delessert Foundation to MS., European Project: 241913,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,FLORINASH(2010), Centre National de la Recherche Scientifique - CNRS (FRANCE), Ecole d'Ingénieurs de Purpan - EIP (FRANCE), Institut National Polytechnique de Toulouse - Toulouse INP (FRANCE), Institut National de la Recherche Agronomique - INRA (FRANCE), Institut National des Sciences Appliquées de Toulouse - INSA (FRANCE), Institut National de la Santé et de la Recherche Médicale - INSERM (FRANCE), Institut universitaire de France - IUF (FRANCE), Université Toulouse III - Paul Sabatier - UT3 (FRANCE), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), ToxAlim (Toulouse, France), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés - LISBP (Toulouse, France), Institut National Polytechnique de Toulouse - INPT (FRANCE), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Neuro-Gastroentérologie & Nutrition (ToxAlim-NGN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Burcelin, Remy, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), Unité de Biométrie et Intelligence Artificielle (ancêtre de MIAT) (UBIA), Institut National de la Recherche Agronomique (INRA), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Service d'hypertension artérielle et thérapeutique [CHU Toulouse] (HTA et thérapeutique), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Simon, Marie Francoise, The role of intestinal microflora in non-alcoholic fatty liver disease (NAFLD) - FLORINASH - - EC:FP7:HEALTH2010-01-01 - 2014-12-31 - 241913 - VALID, Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), and Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)
Subjects: Lipopolysaccharides, Male, mictobiota, White adipose tissue, [SDV.GEN] Life Sciences [q-bio]/Genetics, Gut flora, Fatty Acids, Nonesterified, Intestinal absorption, Cecum, Mice, 0302 clinical medicine, gut, metabolic, background, phenotype, diet, MESH: Diabetes Mellitus, Experimental, MESH: Animals, 2. Zero hunger, 0303 health sciences, Glucose tolerance test, MESH: Muscle, Skeletal, MESH: Cytokines, MESH: Fatty Acids, Nonesterified, medicine.diagnostic_test, biology, digestive, oral, and skin physiology, Gastroenterology, food and beverages, Phenotype, Adaptation, Physiological, Intestines, medicine.anatomical_structure, High-fat diet, Liver, 030220 oncology & carcinogenesis, MESH: Permeability, Cytokines, medicine.symptom, MESH: Intestines, medicine.medical_specialty, MESH: Glucose Tolerance Test, MESH: Intestinal Absorption, Médecine humaine et pathologie, Inflammation, Gut microbiota, Diet, High-Fat, MESH: Phenotype, digestive system, Permeability, Diabetes Mellitus, Experimental, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Diabetes mellitus, Internal medicine, medicine, Animals, Muscle, Skeletal, MESH: Mice, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Metabolic diseases, MESH: Cecum, Glucose Tolerance Test, MESH: Metagenome, medicine.disease, biology.organism_classification, MESH: Adaptation, Physiological, MESH: Male, Mice, Inbred C57BL, MESH: Diet, High-Fat, Endocrinology, Intestinal Absorption, Immunology, Metagenome, MESH: Lipopolysaccharides, MESH: Liver
Abstract: Chantier qualité GA; International audience; OBJECTIVE: The gut microbiota, which is considered a causal factor in metabolic diseases as shown best in animals, is under the dual influence of the host genome and nutritional environment. This study investigated whether the gut microbiota per se, aside from changes in genetic background and diet, could sign different metabolic phenotypes in mice. METHODS: The unique animal model of metabolic adaptation was used, whereby C57Bl/6 male mice fed a high-fat carbohydrate-free diet (HFD) became either diabetic (HFD diabetic, HFD-D) or resisted diabetes (HFD diabetes-resistant, HFD-DR). Pyrosequencing of the gut microbiota was carried out to profile the gut microbial community of different metabolic phenotypes. Inflammation, gut permeability, features of white adipose tissue, liver and skeletal muscle were studied. Furthermore, to modify the gut microbiota directly, an additional group of mice was given a gluco-oligosaccharide (GOS)-supplemented HFD (HFD+GOS). RESULTS: Despite the mice having the same genetic background and nutritional status, a gut microbial profile specific to each metabolic phenotype was identified. The HFD-D gut microbial profile was associated with increased gut permeability linked to increased endotoxaemia and to a dramatic increase in cell number in the stroma vascular fraction from visceral white adipose tissue. Most of the physiological characteristics of the HFD-fed mice were modulated when gut microbiota was intentionally modified by GOS dietary fibres. CONCLUSIONS: The gut microbiota is a signature of the metabolic phenotypes independent of differences in host genetic background and diet.
Published: 2012
Full Text: View/download PDF

40. Correction of RT-qPCR data for genomic DNA-derived signals with ValidPrime

Author: Anne Abot, Jean-François Arnal, Mikael Kubista, Jason S. Iacovoni, Henrik Laurell, Jean-José Maoret, David Svec, Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Gene Expression, Czech Academy of Sciences [Prague] (CAS), TATAA Biocenter AB, Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Faculté de Médecine [Rangueil], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale. Funding for the open access charge: Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France., Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Faculté de Médecine, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]
Subjects: MESH: DNA Primers, MESH: DNA Contamination, Biology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, law, MESH: Mice, Inbred C57BL, MESH: Reverse Transcriptase Polymerase Chain Reaction, Genetics, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, MESH: Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, Polymerase chain reaction, 030304 developmental biology, DNA Primers, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, MESH: Genomics, MESH: DNA, DNA, Genomics, DNA Contamination, Molecular biology, Reverse transcriptase, Mice, Inbred C57BL, genomic DNA, Real-time polymerase chain reaction, Reference sample, chemistry, 13. Climate action, 030220 oncology & carcinogenesis, Methods Online, RNA extraction
Abstract: International audience; Genomic DNA (gDNA) contamination is an inherent problem during RNA purification that can lead to non-specific amplification and aberrant results in reverse transcription quantitative PCR (RT-qPCR). Currently, there is no alternative to RT(-) controls to evaluate the impact of the gDNA background on RT-PCR data. We propose a novel method (ValidPrime) that is more accurate than traditional RT(-) controls to test qPCR assays with respect to their sensitivity toward gDNA. ValidPrime measures the gDNA contribution using an optimized gDNA-specific ValidPrime assay (VPA) and gDNA reference sample(s). The VPA, targeting a non-transcribed locus, is used to measure the gDNA contents in RT(+) samples and the gDNA reference is used to normalize for GOI-specific differences in gDNA sensitivity. We demonstrate that the RNA-derived component of the signal can be accurately estimated and deduced from the total signal. ValidPrime corrects with high precision for both exogenous (spiked) and endogenous gDNA, contributing ∼60% of the total signal, whereas substantially reducing the number of required qPCR control reactions. In conclusion, ValidPrime offers a cost-efficient alternative to RT(-) controls and accurately corrects for signals derived from gDNA in RT-qPCR.
Published: 2012
Full Text: View/download PDF

41. Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue

Author: Flora Picard, Carine Valle, P. Barbe, Jason S. Iacovoni, Nathalie Viguerie, Balbine Roussel, Wim H. M. Saris, Gabby B. Hul, Dominique Langin, Simon, Marie Francoise, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées, Department of Human Biology, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht]-Maastricht University [Maastricht], Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Humane Biologie, RS: NUTRIM - R1 - Metabolic Syndrome, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], and CHU Toulouse [Toulouse]
Subjects: Male, MESH: Serum Amyloid A Protein, Physiology, Adipose tissue, Dexamethasone, ACTIVATION, 0302 clinical medicine, Mineralocorticoid receptor, Longitudinal Studies, MESH: Longitudinal Studies, GENE-EXPRESSION, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, MESH: Muscle, Skeletal, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, C-Reactive Protein, medicine.anatomical_structure, Adipose Tissue, MESH: Dexamethasone, medicine.symptom, Glucocorticoid, MESH: Adipose Tissue, medicine.drug, Adult, medicine.medical_specialty, Adipose tissue macrophages, 030209 endocrinology & metabolism, Inflammation, Biology, METABOLISM, 03 medical and health sciences, Downregulation and upregulation, MICROARRAY, INFLAMMATION, Internal medicine, MESH: C-Reactive Protein, Genetics, medicine, gene expression profiling, Humans, GLUCOCORTICOIDS, Muscle, Skeletal, 030304 developmental biology, Serum Amyloid A Protein, MESH: Humans, Skeletal muscle, 3T3-L1 ADIPOCYTES, MESH: Adult, INSULIN-RESISTANT MICE, MESH: Male, Endocrinology, healthy volunteers, SERUM-AMYLOID-A, CELLS, glucocorticoid, MESH: Glucocorticoids
Abstract: Viguerie N, Picard F, Hul G, Roussel B, Barbe P, Iacovoni JS, Valle C, Langin D, Saris WHM. Multiple effects of a short-term dexamethasone treatment in human skeletal muscle and adipose tissue. Physiol Genomics 44: 141-151, 2012. First published November 22, 2011; doi:10.1152/physiolgenomics.00032.2011.-Glucocorticoids are frequently prescribed drugs with important side-effects such as glucose intolerance and tissue remodeling. The goal was to explore the molecular basis of the response of skeletal muscle and adipose tissue during a short-term dexamethasone treatment to better understand the induction of side-effects of glucocorticoids on these metabolic tissues. Fifteen healthy male subjects were assigned to a 4-day treatment with dexamethasone at 4 mg/day. The primary outcome measures were changes in gene expression profiling of subcutaneous skeletal muscle and adipose tissue. Urinary cortisol, plasma, and metabolic biochemistry were also assessed. In both tissues the prominent observation was a response to stress and increased inflammatory responses. An upregulation of the serum amyloid A was detected in skeletal muscle, adipose tissue, and plasma, whereas circulating levels of C reactive protein, another acute phase protein, decreased along with a worsened insulin sensitivity index. As tissue-specific features, tissue remodeling was shown in skeletal muscle while the adipose tissue exhibited a decreased energy metabolism. Several limitations might be raised due to the small number of subjects investigated: a possible cross talk with the mineralocorticoid receptor, and a single time point may not identify regulations occurring during longitudinal treatment. In line with the known physiological effect of glucocorticoids the early modulation of stress response genes was observed. An unexpected feature was the upregulation of the inflammatory and immune pathways. The identification of novel impact on two glucocorticoid target tissues provides a molecular basis for the design of more specific glucocorticoids devoid of adverse effects.
Published: 2012
Full Text: View/download PDF

42. Involvement of tissue bacteria in the onset of diabetes in humans: evidence for a concept

Author: Pascale Klopp, Jason S. Iacovoni, Joël Doré, Céline Lange, Olivier Bouchez, Rémy Burcelin, Jérôme Mariette, Jacques Amar, Olivier Lantieri, Marie-Aline Charles, Matteo Serino, L. Perez, Christophe Klopp, Michael Courtney, B. Balkau, Michel Marre, Chantal Chabo, Patricia Lepage, Stanislas Mondot, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Médecine Interne et Hypertension Artérielle [Toulouse], CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Unité de Biométrie et Intelligence Artificielle de Toulouse [Castanet-Tolosan] (UBIA), Institut National de la Recherche Agronomique (INRA)-Plateforme bioinformatique du GIS GENOTOUL - Génopole Toulouse Midi-Pyrénées, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Vaiomer, Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut inter-Régional pour la SAnté (IRSA), This work was funded by the Agence Nationale de la Recherche (French national research agency) (to R. Burcelin) and by the Societe Francophone de Diabete (to B. Balkau). The D.E.S.I.R. study has been supported by Inserm contracts with CNAMTS, Lilly, Novartis Pharma and sanofi-aventis, by Inserm (Reseaux en Sante Publique, Interactions entre les determinants de la sante, Cohortes Sante TGIR 2008), the Association Diabete Risque Vasculaire, the Federation Francaise de Cardiologie, La Fondation de France, ALFEDIAM, ONIVINS, Societe Francophone du Diabete, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics., Service d'hypertension artérielle et thérapeutique [CHU Toulouse] (HTA et thérapeutique), Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biométrie et Intelligence Artificielle (ancêtre de MIAT) (UBIA), Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), VAIOMER SAS, VAIOMMER, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), and Plateforme bioinformatique du GIS GENOTOUL - Génopole Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)
Subjects: Male, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], [MATH] Mathematics [math], 0302 clinical medicine, MESH: Metabolic Syndrome X, RNA, Ribosomal, 16S, MESH: Obesity, Longitudinal Studies, [MATH]Mathematics [math], MESH: Longitudinal Studies, Genetics, MESH: Aged, Metabolic Syndrome, 0303 health sciences, education.field_of_study, MESH: Middle Aged, biology, Middle Aged, MESH: Case-Control Studies, 3. Good health, [SDV] Life Sciences [q-bio], MESH: RNA, Ribosomal, 16S, Obesity, Abdominal, Female, France, MESH: Diabetes Mellitus, Type 2, Adult, Population, abdominal adiposity, 030209 endocrinology & metabolism, [INFO] Computer Science [cs], MESH: Obesity, Abdominal, 03 medical and health sciences, endocrinology, Diabetes mellitus, Internal Medicine, medicine, microbiota, Humans, [INFO]Computer Science [cs], Obesity, education, 16s rdna gene, 030304 developmental biology, Aged, MESH: Humans, Bacteria, Case-control study, MESH: Biological Markers, MESH: Adult, Human physiology, MESH: Metagenome, biology.organism_classification, medicine.disease, MESH: Male, MESH: France, MESH: Bacteria, Diabetes Mellitus, Type 2, Case-Control Studies, Immunology, Metagenome, metabolism, MESH: Female, Biomarkers
Abstract: Chantier qualité GA; International audience; AIMS/HYPOTHESIS: Evidence suggests that bacterial components in blood could play an early role in events leading to diabetes. To test this hypothesis, we studied the capacity of a broadly specific bacterial marker (16S rDNA) to predict the onset of diabetes and obesity in a general population. METHODS: Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) is a longitudinal study with the primary aim of describing the history of the metabolic syndrome. The 16S rDNA concentration was measured in blood at baseline and its relationship with incident diabetes and obesity over 9 years of follow-up was assessed. In addition, in a nested case-control study in which participants later developed diabetes, bacterial phylotypes present in blood were identified by pyrosequencing of the overall 16S rDNA gene content. RESULTS: We analysed 3,280 participants without diabetes or obesity at baseline. The 16S rDNA concentration was higher in those destined to have diabetes. No difference was observed regarding obesity. However, the 16S rDNA concentration was higher in those who had abdominal adiposity at the end of follow-up. The adjusted OR (95% CIs) for incident diabetes and for abdominal adiposity were 1.35 (1.11, 1.60), p = 0.002 and 1.18 (1.03, 1.34), p = 0.01, respectively. Moreover, pyrosequencing analyses showed that participants destined to have diabetes and the controls shared a core blood microbiota, mostly composed of the Proteobacteria phylum (85-90%). CONCLUSIONS/INTERPRETATION: 16S rDNA was shown to be an independent marker of the risk of diabetes. These findings are evidence for the concept that tissue bacteria are involved in the onset of diabetes in humans.
Published: 2011
Full Text: View/download PDF

43. Blood signature of pre-heart failure: a microarrays study

Author: Fatima Smih, Michel Galinier, Romain Harmancey, Charlotte Trouillet, Olivier Lairez, Pierre Massabuau, Clément Delmas, Annie Turkieh, Matthieu Berry, Jean Ferrières, Atul Pathak, Jason S. Iacovoni, Franck Desmoulin, Philippe Rouet, François Koukoui, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie [Toulouse], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], This work was supported by the National Research Agency and Fondation de France., Simon, Marie Francoise, Service Cardiologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Male, Microarrays, lcsh:Medicine, 030204 cardiovascular system & hematology, Cardiovascular, Bioinformatics, Diagnostic Radiology, Ventricular Dysfunction, Left, 0302 clinical medicine, Risk Factors, Natriuretic Peptide, Brain, Pathology, Leukocytes, lcsh:Science, Oligonucleotide Array Sequence Analysis, Principal Component Analysis, 0303 health sciences, education.field_of_study, Multidisciplinary, Medical treatment, Statistics, Models, Cardiovascular, Genomics, Middle Aged, Clinical Laboratory Sciences, Functional Genomics, 3. Good health, Echocardiography, Cardiology, Medicine, Female, DNA microarray, medicine.symptom, Radiology, Research Article, Adult, medicine.medical_specialty, Population, Biostatistics, Asymptomatic, Young Adult, 03 medical and health sciences, Diagnostic Medicine, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, education, Biology, Aged, 030304 developmental biology, Heart Failure, Receiver operating characteristic, business.industry, Gene Expression Profiling, lcsh:R, Computational Biology, Reproducibility of Results, medicine.disease, Gene expression profiling, Gene Expression Regulation, ROC Curve, Heart failure, lcsh:Q, Genome Expression Analysis, business, Preclinical stage, Mathematics, Biomarkers, Software, General Pathology
Abstract: International audience; BACKGROUND: The preclinical stage of systolic heart failure (HF), known as asymptomatic left ventricular dysfunction (ALVD), is diagnosed only by echocardiography, frequent in the general population and leads to a high risk of developing severe HF. Large scale screening for ALVD is a difficult task and represents a major unmet clinical challenge that requires the determination of ALVD biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: 294 individuals were screened by echocardiography. We identified 9 ALVD cases out of 128 subjects with cardiovascular risk factors. White blood cell gene expression profiling was performed using pangenomic microarrays. Data were analyzed using principal component analysis (PCA) and Significant Analysis of Microarrays (SAM). To build an ALVD classifier model, we used the nearest centroid classification method (NCCM) with the ClaNC software package. Classification performance was determined using the leave-one-out cross-validation method. Blood transcriptome analysis provided a specific molecular signature for ALVD which defined a model based on 7 genes capable of discriminating ALVD cases. Analysis of an ALVD patients validation group demonstrated that these genes are accurate diagnostic predictors for ALVD with 87% accuracy and 100% precision. Furthermore, Receiver Operating Characteristic curves of expression levels confirmed that 6 out of 7 genes discriminate for left ventricular dysfunction classification. CONCLUSIONS/SIGNIFICANCE: These targets could serve to enhance the ability to efficiently detect ALVD by general care practitioners to facilitate preemptive initiation of medical treatment preventing the development of HF.
Published: 2011
Full Text: View/download PDF

44. Tubulopathie post-rhabdomyolyse : polarisation biphasique et rôle des macrophages du rein

Author: J.P. Schanstra, Jean-Loup Bascands, L. Ducasse, Dominique Chauveau, Frédéric Martins, Alexia Zakaroff-Girard, Céline Guilbeau-Frugier, B. Pipy, Audrey Casemayou, Bénédicte Buffin-Meyer, Julie Belliere, and Jason S. Iacovoni
Subjects: Nephrology
Abstract: Introduction L’insuffisance renale aigue (IRA) secondaire a une rhabdomyolyse est frequente et represente 10 % des IRA. La tubulopathie est principalement attribuee au role deletere de la myoglobine. Nous avons fait l’hypothese que cette agression renale impliquait des macrophages, polarises vers le phenotype M1 (pro-inflammatoire) ou M2 (reparateur). Materiels et methodes Dans un modele murin, la rhabdomyolyse est induite par injection intramusculaire de glycerol. Les macrophages renaux sont caracterises a l’aide de 9 marqueurs de surface, et par PCR quantitative sur cellules uniques pour analyse transcriptionnelle. Le clodronate liposomal (CL) est utilise pour depleter les macrophages. L’effet de la myoglobine sur les cellules epitheliales et des macrophages en culture primaires est evalue in vitro. Resultats Le phenotype des macrophages du rein varie en fonction du temps. A j2 apres la rhabdomyolyse, des macrophages pro-inflammatoires M1 sont massivement recrutes, alors qu’a j8, d’autres macrophages de phenotype M2 reparateur, deviennent predominants. Le traitement par CL reduit la mortalite par insuffisance renale des souris, et revele le role-cle des macrophages pro-inflammatoires secretant des composants de la matrice extracellulaire (fibronectine, collagene III), et des chemo-attractants (CCL-2, CCL-7). La myoglobine per se entraine la production de chemo-attractants par les tubulocytes renaux et les macrophages, et polarise ces derniers vers un phenotype M1. A J30, alors que la fonction renale est globalement restauree, on note une fibrose tubulo-interstitielle majeure, qui est significativement prevenue par le traitement par CL. Discussion et conclusion Ces donnees mettent en evidence : (i) le role determinant des macrophages inflammatoires M1 dans la physiopathologie et le pronostic de l’IRA post-rhabdomyolyse murine ; (ii) l’existence de lesions de fibrose renale persistante apres recuperation fonctionnelle.
Published: 2014
Full Text: View/download PDF

45. FAN stimulates TNF(alpha)-induced gene expression, leukocyte recruitment, and humoral response

Author: Marie-Antoinette Bertrand, Pascal G.P. Martin, Caroline Nevoit, Thierry Levade, Marie-Claude Trombe, Hervé Benoist, Victorine Douin-Echinard, Marie-Hélène Bessières, Bruno Ségui, Nicole Therville, Anne Montfort, Virginie Garcia, Jason S. Iacovoni, Bénédicte de Badts, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique (INRA), IFR 31 Louis Bugnard (IFR 31), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service de Parasitologie-Mycologie [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Faculté des Sciences Pharmaceutiques, Service de Parasitologie et Mycologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Chemokine, Chemokine CXCL2, Type I, Gene Expression, Inbred C57BL, MESH: Listeria monocytogenes, MESH: Mice, Knockout, MESH: Recombinant Proteins, Mice, 0302 clinical medicine, Gene expression, Receptors, Immunology and Allergy, Listeriosis, MESH: Animals, MESH: Pneumococcal Infections, Peritoneal Cavity, Cells, Cultured, Mice, Knockout, Listeria Infections, MESH: Receptors, Tumor Necrosis Factor, Type I, 0303 health sciences, Cultured, biology, MESH: Toxoplasma, Intracellular Signaling Peptides and Proteins, MESH: Peritoneal Cavity, Acquired immune system, Recombinant Proteins, MESH: Antibody Formation, medicine.anatomical_structure, Streptococcus pneumoniae, Neutrophil Infiltration, Receptors, Tumor Necrosis Factor, Type I, 030220 oncology & carcinogenesis, Knockout mouse, MESH: Toxoplasmosis, Tumor necrosis factor alpha, Toxoplasma, MESH: Listeria Infections, Toxoplasmosis, MESH: Streptococcus pneumoniae, MESH: Cells, Cultured, MESH: Gene Expression, Knockout, Cells, Immunology, Spleen, Pneumococcal Infections, 03 medical and health sciences, Peritoneal cavity, MESH: Mice, Inbred C57BL, MESH: Intracellular Signaling Peptides and Proteins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, MESH: Chemokine CXCL2, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, 030304 developmental biology, Microarray analysis techniques, Interleukin-6, Tumor Necrosis Factor-alpha, Fibroblasts, Microarray Analysis, Molecular biology, Listeria monocytogenes, MESH: Interleukin-6, Mice, Inbred C57BL, MESH: Microarray Analysis, MESH: Neutrophil Infiltration, MESH: Fibroblasts, MESH: Tumor Necrosis Factor-alpha, Antibody Formation, biology.protein, Tumor Necrosis Factor, human activities
Abstract: Factor associated with neutral sphingomyelinase activation (FAN) is an adaptor protein that constitutively binds to TNF-R1. Microarray analysis was performed in fibroblasts derived from wild-type or FAN knockout mouse embryos to evaluate the role of FAN in TNF-induced gene expression. Approximately 70% of TNF-induced genes exhibited lower expression levels in FAN-deficient than in wild-type fibroblasts. Of particular interest, TNF-induced expression of cytokines/chemokines, such as IL-6 and CXCL-2, was impaired in FAN-deficient cells. This was confirmed by real time RT-PCR and ELISA. Upon i.p. TNF or thioglycollate injection, neutrophil recruitment into the peritoneal cavity was reduced by more than 50% in FAN-deficient mice. Nevertheless, FAN-deficient animals did not exhibit an increased susceptibility to different microorganisms including bacteria and parasites, indicating that FAN is not essential for pathogen clearance. Specific Ab response to BSA was substantially impaired in FAN-deficient mice and this was associated with a reduced content of leukocytes in the spleen of BSA-challenged FAN-deficient mice as compared with their wild-type counterparts. Altogether, our results indicate the involvement of FAN in TNF-induced gene expression and leukocyte recruitment, contributing to the establishment of the specific immune response.
Published: 2009
Full Text: View/download PDF

46. The VEGF IRESes are differentially susceptible to translation inhibition by miR-16

Author: Hervé Prats, Eric Lacazette, Amandine Bastide, Zeïneb S. Karaa, Christian Touriol, Jason S. Iacovoni, Simon, Marie Francoise, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Gene isoform, Vascular Endothelial Growth Factor A, Biology, Report, microRNA, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Protein biosynthesis, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Binding site, Molecular Biology, 3' Untranslated Regions, Regulation of gene expression, MESH: Humans, Binding Sites, Three prime untranslated region, MESH: Vascular Endothelial Growth Factor A, fungi, Translation (biology), MESH: 3' Untranslated Regions, MESH: Gene Expression Regulation, Molecular biology, Cell biology, MESH: Hela Cells, Internal ribosome entry site, MicroRNAs, MESH: Binding Sites, Gene Expression Regulation, MESH: Protein Biosynthesis, Protein Biosynthesis, MESH: MicroRNAs, MESH: Ribosomes, Ribosomes, HeLa Cells
Abstract: International audience; Experiments with EMCV (Encephalomyocarditis virus) internal ribosome entry sites (IRESes) have shown that microRNAs (miRs) are unable to inhibit IRES driven translation. However, it is accepted that miRs can inhibit translation through multiple mechanisms, only some of which require interaction with the 5' cap structure. In this report, we first validate the targeting of miR-16 to a predicted binding site in the VEGF 3'UTR. We developed a series of experiments to ascertain whether or not miR-16 can inhibit translation of transcripts driven by either of the VEGF IRESes. Our results indicate that cellular IRESes can be classified as both sensitive and insensitive to miR control. While VEGF IRES-A activity was not altered by miR-16 targeting to the 3'UTR, IRES-B was susceptible to miR-16 inhibition. Taken together with previous results that show that IRES-B selectively translates the CUG initiated VEGF-121 isoform, we can conclude that the existence of two differentially susceptible IRESes in the VEGF 5'UTR leads to even more complex regulatory control of VEGF isoform production. This study demonstrates for the first time the inhibition of cellular IRES driven translation by a miR.
Published: 2009
Full Text: View/download PDF

47. Control of the vascular endothelial growth factor internal ribosome entry site (IRES) activity and translation initiation by alternatively spliced coding sequences

Author: Catherine Zanibellato, Christian Touriol, Mathieu Boulard, Stéphanie Bornes, Jason S. Iacovoni, Hervé Prats, and Corinne Hieblot
Subjects: Vascular Endothelial Growth Factor A, Five prime untranslated region, Molecular Sequence Data, Codon, Initiator, Biology, Biochemistry, Exon, Eukaryotic translation, Start codon, Eukaryotic initiation factor, Humans, RNA, Messenger, Peptide Chain Initiation, Translational, Molecular Biology, Genetics, Base Sequence, fungi, Alternative splicing, Cell Biology, Exons, Internal ribosome entry site, Alternative Splicing, Protein Biosynthesis, RNA splicing, 5' Untranslated Regions, Ribosomes, HeLa Cells
Abstract: The vascular endothelial growth factor-A (VEGF) gene locus contains eight exons that span 14 kb. Alternative splicing generates multiple, different mRNAs that in turn translate into at least five protein isoforms. While the canonical AUG start codon is located at position 1039 in exon 1, there also exists an upstream, in-frame CUG initiation codon that drives expression of L-VEGF, containing an additional 180 amino acids. Two separate internal ribosome entry sites (IRES) regulate the activity of each initiation codon. Thus the 5′-UTR of VEGF, which comprises the majority of exon 1, consists of IRES B, the CUG, IRES A, and the AUG, from 5′ to 3′. Previously, it has been shown that IRES B regulates initiation at the CUG and IRES A regulates AUG usage. In this study, we have found evidence that the exon content of the VEGF mRNA, determined through alternative splicing, controls IRES A activity. While the CUG is most efficient at initiating translation, transcripts that lack both exons 6 and 7 and therefore contain an exon 5/8 junction lack AUG-initiated translation. The process of splicing is not responsible for this start codon selection since transfection of genomic and cDNA VEGF sequences give the same expression pattern. We hypothesize that long range tertiary interactions in the VEGF mRNA regulate IRES activity and thus control start codon selection. This is the first report describing the influence of alternatively spliced coding sequences on codon selection by modulating IRES activity.
Published: 2004

48. Identification of novel binding elements and gene targets for the homeodomain protein BARX2

Author: David B. Edelman, Robyn Meech, Tracy A. Stevens, and Jason S. Iacovoni
Subjects: Transcription, Genetic, Sequence analysis, Amino Acid Motifs, DNA Mutational Analysis, Genetic Vectors, Molecular Sequence Data, Biology, Transfection, Biochemistry, Cell Line, Mice, Cell Line, Tumor, Gene expression, Transcriptional regulation, Cell Adhesion, Animals, Humans, Cloning, Molecular, Luciferases, Promoter Regions, Genetic, Molecular Biology, Transcription factor, Gene, Cytoskeleton, Homeodomain Proteins, Binding Sites, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Cell Biology, DNA, Sequence Analysis, DNA, Molecular biology, Precipitin Tests, Chromatin, Protein Structure, Tertiary, DNA binding site, RNA Interference, Chromatin immunoprecipitation, Cell Division, Software, Protein Binding, Transcription Factors
Abstract: BARX2 is a homeobox transcription factor that influences cellular differentiation in various developmental contexts. To begin to identify the gene targets that mediate its effects, chromatin immunoprecipitation (ChIP) was used to isolate BARX2 binding sites from the human MCF7 breast cancer cell line. Cloning and sequencing of BARX2-ChIP-derived DNA fragments identified 60 potential BARX2 target loci that were proximal to or within introns of genes involved in cytoskeletal organization, cell adhesion, growth factor signaling, transcriptional regulation, and RNA metabolism. The sequences of over half of the fragments showed homology with the mouse genome, and several sequences could be mapped to orthologous human and mouse genes. Binding of BARX2 to 21 genomic loci examined was confirmed quantitatively by replicate ChIP assays. A combination of sequence analysis and electrophoretic mobility shift assays revealed homeodomain binding sites within several fragments that bind to BARX2 in vitro. The majority of BARX2 binding fragments tested (14/19), also affected transcription in luciferase reporter gene assays. Mutation analyses of three fragments showed that their transcriptional activities required the HBS, and suggested that BARX2 regulates gene expression by binding to DNA elements containing paired TAAT motifs that are separated by a poly(T) sequence. Inhibition of BARX2 expression in MCF7 cells led to reduced expression of eight genes associated with BARX2 binding sites, indicating that BARX2 directly regulates their expression. The data suggest that BARX2 can coordinate the expression of a network of genes that influence the growth of MCF7 cells.
Published: 2004

49. A new inducible protein expression system in fission yeast based on the glucose-repressed inv1 promoter

Author: Jason S. Iacovoni, Frédérique Gaits, and Paul Russell
Subjects: Sucrose, Glycoside Hydrolases, Transcription, Genetic, Genetic Vectors, chemistry.chemical_compound, Gene Expression Regulation, Fungal, Schizosaccharomyces, Genetics, Promoter Regions, Genetic, Gene, Derepression, Regulation of gene expression, Growth medium, Expression vector, biology, beta-Fructofuranosidase, General Medicine, biology.organism_classification, Yeast, Culture Media, Repressor Proteins, Invertase, Glucose, chemistry, Biochemistry, Schizosaccharomyces pombe, Plasmids
Abstract: Studies of the fission yeast Schizosaccharomyces pombe have made major contributions towards understanding cell-cycle control and many other important aspects of cell biology. A series of pREP expression vectors that utilize the thiamine-repressible nmt1 promoter are used routinely to manipulate the expression of genes in fission yeast. A shortcoming of the nmt1 promoter is that it is very slowly induced following removal of thiamine from the growth medium, requiring approx. 16h for full induction. Invertase, an enzyme responsible for sucrose metabolism, is regulated transcriptionally by glucose derepression in S. pombe. Using the inv1 promoter, we have developed the pINV1 set of inducible protein expression vectors. A shift from glucose to sucrose-based culture medium leads to a very rapid induction of the inv1 promoter. Genes that are regulated by the inv1 promoter are fully induced within 1h of the shift to sucrose-based medium. The pINV1 vectors utilize a simple induction protocol and enable studies in fission yeast requiring tight and rapid regulation of protein synthesis.
Published: 1999

50. Hormone-regulatable neoplastic transformation induced by a Jun-estrogen receptor chimera

Author: Ulrich Kruse, Martin E. Goller, Jason S. Iacovoni, and Peter K. Vogt
Subjects: Regulation of gene expression, Multidisciplinary, Binding protein, Recombinant Fusion Proteins, Estrogen receptor, Estrogens, Chick Embryo, Biology, Biological Sciences, Fibroblasts, Fusion protein, Molecular biology, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Genes, jun, Receptors, Estrogen, Gene Targeting, Animals, Humans, Neoplastic transformation, Receptor, Transcription factor, Gene, Cells, Cultured
Abstract: The v- jun oncogene encodes a nuclear DNA binding protein that functions as a transcription factor and is part of the activator protein 1 complex. Oncogenic transformation by v- jun is thought to be mediated by the aberrant expression of specific target genes. To identify such Jun-regulated genes and to explore the mechanisms by which Jun affects their expression, we have fused the full-length v-Jun and an amino-terminally truncated form of v-Jun to the hormone-binding domain of the human estrogen receptor. The two chimeric proteins function as ligand-inducible transactivators. Expression of the fusion proteins in chicken embryo fibroblasts causes estrogen-dependent transformation.
Published: 1997

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

62 results on '"Jason S Iacovoni"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources