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7 results on '"Hématopoïèse normale et pathologique (U1170 Inserm)"'

1. CABLES1 Deficiency Impairs Quiescence and Stress Responses of Hematopoietic Stem Cells in Intrinsic and Extrinsic Manners

Author

Viviane Baral, Liang He, Mallorie Depond, Fawzia Louache, Florian Beghi, Yanyan Zhang, Virginie Joulin, M. Wittner, Patrick Gonin, Adlen Foudi, Bo R. Rueda, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Lipopolysaccharides, 0301 basic medicine, Aging, hematopoietic niches, Antigens, CD34, Biochemistry, Mice, 0302 clinical medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], RNA, Small Interfering, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, lcsh:R5-920, p21, Hematopoietic Stem Cell Transplantation, hematopoietic stem cell homeostasis, Cell biology, Haematopoiesis, medicine.anatomical_structure, cell cycle, RNA Interference, Fluorouracil, Stem cell, mesenchymal stromal cells, lcsh:Medicine (General), Cyclin-Dependent Kinase Inhibitor p21, Bone Marrow Cells, Biology, Article, 03 medical and health sciences, Cyclins, Genetics, medicine, Animals, Humans, Peripheral blood cell, Progenitor cell, Cell Proliferation, Hematopoietic stem cell homeostasis, Mesenchymal stem cell, Cell Cycle Checkpoints, Cell Biology, Hematopoietic Stem Cells, Hematopoiesis, Mice, Inbred C57BL, Transplantation, 030104 developmental biology, lcsh:Biology (General), CABLES1, Bone marrow, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Summary Bone marrow (BM) niche cells help to keep adult hematopoietic stem cells (HSCs) in a quiescent state via secreted factors and induction of cell-cycle inhibitors. Here, we demonstrate that the adapter protein CABLES1 is a key regulator of long-term hematopoietic homeostasis during stress and aging. Young mice lacking Cables1 displayed hyperproliferation of hematopoietic progenitor cells. This defect was cell intrinsic, since it was reproduced in BM transplantation assays using wild-type animals as recipients. Overexpression and short hairpin RNA-mediated depletion of CABLES1 protein resulted in p21Cip/waf up- and downregulation, respectively. Aged mice lacking Cables1 displayed abnormalities in peripheral blood cell counts accompanied by a significant reduction in HSC compartment, concomitant with an increased mobilization of progenitor cells. In addition, Cables1−/− mice displayed increased sensitivity to the chemotherapeutic agent 5-fluorouracil due to an abnormal microenvironment. Altogether, our findings uncover a key role for CABLES1 in HSC homeostasis and stress hematopoiesis., Graphical Abstract, Highlights • CABLES1 is expressed in immature hematopoietic progenitor cells and niche cells • CABLES1 in an intrinsic negative cell-cycle regulator of hematopoietic progenitor cells • CABLES1 regulates p21Cip/waf protein levels • The abnormal stress responses of Cables1−/− HSC during aging are niche cell dependent, Maintenance of hematopoietic stem cell quiescence is crucial for homeostasis. Using mutant mice and cross-transplant experiments, Louache and colleagues show that the adapter protein CABLES1 is required for stem cell quiescence under transplantation and regulates p21Cip/waf protein level. In addition, CABLES1 is a niche-based regulator of hematopoietic stem cell responses to proliferative stress and during aging.

Published
2019
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2. Turning off NADPH oxidase-2 by impeding p67phox activation in infected mouse macrophages reduced viral entry and inflammation

Author

Edna Bechor, Pierre Adenot, Jasmina Vidic, Nicolas Bertho, Vijay M. Khedkar, Nathalie Lejal, Stéphanie Solier, Edgar Pick, Sandrine Truchet, Edwige Bouguyon, Anny Slama-Schwok, Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Université Paris Saclay (COmUE), Sackler Faculty of Medicine, Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Plateforme MIMA2, Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-14-CE09-0017-02, Bioasia 35976PH

Subjects
0301 basic medicine, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], viruses, Biophysics, Inflammation, Endocytosis, Biochemistry, 03 medical and health sciences, Immune system, Viral entry, medicine, NADPH oxidase‑2, Molecular Biology, NADPH oxidase, 030102 biochemistry & molecular biology, biology, Chemistry, Activator (genetics), Confocal imaging, 3. Good health, Cell biology, Protein-protein and protein-ligand interactions, Kinetics, Influenza A virus entry, 030104 developmental biology, cardiovascular system, biology.protein, Tumor necrosis factor alpha, medicine.symptom, Intracellular, circulatory and respiratory physiology
Abstract

International audience; Background: Targeting cells of the host immune system is a promising approach to fight against Influenza A virus (IAV) infection. Macrophage cells use the NADPH oxidase-2 (NOX2) enzymatic complex as a first line of defense against pathogens by generating superoxide ions O-2(-) and releasing H2O2. Herein, we investigated whether targeting membrane-embedded NOX2 decreased IAV entry via raft domains and reduced inflammation in infected macrophages. Methods: Confocal microscopy and western blots monitored levels of the viral nucleoprotein NP and p67(Phox), NOX2 activator subunit, Elisa assays quantified TNF-alpha levels in LPS or IAV-activated mouse or porcine alveolar macrophages pretreated with a fluorescent NOX inhibitor, called nanoshutter NS1. Results: IAV infection in macrophages promoted p67(Phox) translocation to the membrane, rafts clustering and activation of the NOX2 complex at early times. Disrupting rafts reduced intracellular viral NP. NS1 markedly reduced raft clustering and viral entry by binding to the C-terminal of NOX2 also characterized in vitro. NS1 decrease of TNF-a release depended on the cell type. Conclusion: NOX2 participated in IAV entry and raft-mediated endocytosis. NOX2 inhibition by NS1 reduced viral entry. NS1 competition with p67(Phox) for NOX2 binding shown by in silico models and cell-free assays was in agreement with NS1 inhibiting p67(Phox) translocation to membrane-embedded NOX2 in mouse and porcine macrophages. General significance: We introduce NS1 as a compound targeting NOX2, a critical enzyme controlling viral levels and inflammation in macrophages and discuss the therapeutic relevance of targeting the C-terminal of NADPH oxidases by probes like NS1 in viral infections.

Published
2018
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3. Causes and Consequences of Microtubule Acetylation

Author

Guillaume Montagnac, Carsten Janke, Institut Curie [Paris], Stress génotoxiques et cancer, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Paris-Sud - Paris 11 (UP11), Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Lysine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Microtubules, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Microtubule, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cytoskeleton, 030102 biochemistry & molecular biology, biology, Structural integrity, Acetylation, Microtubule lumen, Biomechanical Phenomena, Cell biology, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, 030104 developmental biology, Tubulin, biology.protein, Tubulin acetylation, Stress, Mechanical, General Agricultural and Biological Sciences, Protein Processing, Post-Translational
Abstract

Among the different types of cytoskeletal components, microtubules arguably accumulate the greatest diversity of post-translational modifications (PTMs). Acetylation of lysine 40 (K40) of α-tubulin has received particular attention because it is the only tubulin PTM to be found in the lumen of microtubules: most other tubulin PTMs are found at the outer surface of the microtubule. As a consequence, the enzyme catalyzing K40 acetylation needs to penetrate the narrow microtubule lumen to find its substrate. Acetylated microtubules have been considered to be stable, long-lived microtubules; however, until recently, there was little information about whether the longevity of these microtubules is the cause or the consequence of acetylation. Current advances suggest that this PTM helps the microtubule lattice to cope with mechanical stress, thus facilitating microtubule self-repair. These observations now shed new light on the structural integrity of microtubules, as well as on the mechanisms and biological functions of tubulin acetylation. Here, we discuss recent insights into how acetylation is generated in the lumen of microtubules, and how this 'hidden' PTM can control the properties and functions of microtubules.

Published
2017
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4. ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia

Author

Arnaud Petit, Françoise Pflumio, Cécile Thirant, Cécile K. Lopez, Sébastien Malinge, Hana Raslova, Aurelie Siret, Olivier A. Bernard, Clarisse Thiollier, Cathy Ignacimouttou, Mehdi Khaled, M'Boyba Diop, Jürg Schwaller, William Vainchenker, John D. Crispino, Paola Ballerini, Guy Leverger, Ce ' Line Lefebvre, Philippe Rameau, Benjamin T. Kile, Catherine Carmichael, Lou Le Mouel, Eric Soler, Phillipe Dessen, Thomas Mercher, Zakia Aid, Julie Riviere, Nathalie Droin, Christian Wichmann, Camille Lobry, Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Plateforme imagerie et cytométrie ( PFIC ), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse ( AMMICa ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ondes et Imagerie ( O&I ), Laboratoire de Mécanique et d'Acoustique [Marseille] ( LMA ), Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ), Hôpital Trousseau, CHRU Tours, CHU Trousseau [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ), Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Northwestern University Chicago, Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ), Plateforme de génomique, Laboratoire des Adaptations Physiologiques aux Activités Physiques ( LAPHAP ), Université de Poitiers, Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), and Université de Lyon-Université de Lyon

Subjects
Transcriptional Activation, 0301 basic medicine, Cancer Research, Oncogene Proteins, Fusion, ChIP, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, Acute megakaryoblastic leukemia, Transcriptional Regulator ERG, GLIS2, Downregulation and upregulation, Leukemia, Megakaryoblastic, Acute, Transcription (biology), medicine, Animals, Humans, GATA1 Transcription Factor, Child, Enhancer, Gene, Transcription factor, transcription factor, CBFA2T3, AMKL, leukemia, Cell Differentiation, GLIS, medicine.disease, Leukemia, pediatric, Enhancer Elements, Genetic, 030104 developmental biology, Oncology, ERG, CRISPR, Cancer research, enhancer
Abstract

International audience; Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.

Published
2017
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5. TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis

Author

Lise Secardin, William Vainchenker, Olivier Bernard, Alexander A. Ishchenko, Murat Saparbaev, Emna Mahfoudhi, Philippe Rameau, Véronique Della Valle, Ibtissam Talhaoui, Isabelle Plo, Xenia Cabagnols, Salem Abbes, Hématopoïèse normale et pathologique (UMR 1170 ), Université Paris-Sud - Paris 11 (UP11) - Institut Gustave Roussy (IGR) - Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'hématologie moléculaire et cellulaire, institut Pasteur de Tunis, Institut Pasteur de Tunis - Réseau International des Instituts Pasteur, Institut Gustave Roussy (IGR), Réparation de l’ADN (CNRS UMR 8200), This work was supported by grants from Agence Nationale de la Recherche (ANR-Blanc 2013 GERMPN) to IP and [ANR Blanc 2010 Project ANR-10-BLAN-1617] to IP and MS, Association pour la Recherche contre le Cancer (ARC) (ARC libre 2012) to IP, Electricité de France (http://www.edf.fr) RB 2014-26 to MS and Fondation de France (http://www.fondationdefrance.org) [#2012 00029161] to AAI. Labex GR-Ex (IP, WV) is funded by the program 'Investissements d’avenir'. EM was funded by INSERM/DGRST then a grant from Institut Pasteur from Tunis, Tunisia. LS were supported by Ph.D grants from the Cancéropôle Région Ile de France (DIM cellule souche). XC was supported by Ph.D MENRT grant. IT was supported by postdoctoral fellowship from the Fondation ARC (http://www.arc-cancer.net) PDF20110603195., ANR-Blanc 2013 GERMPN, GERMPN, ANR-10-BLAN-1617, EPIGENOME, Formation, dynamics and epigenetic functions of 5-hydroxymethylcytosine residues in DNA.(2010), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tunis El Manar (UTM), Laboratoire d'hématologie moléculaire et cellulaire (LR11IPT07), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Plateforme imagerie et cytométrie (PFIC), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie, Institut Pasteur de Tunis, This work was supported by grants from Agence Nationale de la Recherche (ANR-Blanc 2013 GERMPN) to IP and [ANR Blanc 2010 Project ANR-10-BLAN-1617] to IP and MS, Association pour la Recherche contre le Cancer (ARC) (ARC libre 2012) to IP, Electricité de France (http://www.edf.fr) RB 2014-26 to MS and Fondation de France (http://www.fondationdefrance.org) [#2012 00029161] to AAI. Labex GR-Ex (IP, WV) is funded by the program 'Investissements d’avenir'. EM was funded by INSERM/DGRST then a grant from Institut Pasteur from Tunis, Tunisia. LS were supported by Ph.D grants from the Cancéropôle Région Ile de France (DIM cellule souche). XC was supported by Ph.D MENRT grant. IT was supported by postdoctoral fellowship from the Fondation ARC., We thank the cytometry platform of Gustave Roussy (Y. Lecluse)., ANR-10-BLAN-1617,EPIGENOME,Formation, dynamics and epigenetic functions of 5-hydroxymethylcytosine residues in DNA.(2010), ANR-13-JSV1-0007,GERMPN,Etude des cas familiaux de néoplasmes myéloproliférifs: recherche des anomalies génétiques et de leurs fonctions.(2013), Pasteur Tunis, Institut, BLANC - Formation, dynamics and epigenetic functions of 5-hydroxymethylcytosine residues in DNA. - - EPIGENOME2010 - ANR-10-BLAN-1617 - BLANC - VALID, Jeunes Chercheuses et Jeunes Chercheurs - Etude des cas familiaux de néoplasmes myéloproliférifs: recherche des anomalies génétiques et de leurs fonctions. - - GERMPN2013 - ANR-13-JSV1-0007 - JC - VALID, and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, DNA Repair, Genetic instability, MESH: Fibroblasts/cytology, MESH: Tumor Suppressor Protein p53/metabolism, MESH: Fibroblasts/metabolism, MESH: Mutagenesis, MESH: Base Sequence, MESH: Thymine DNA Glycosylase/deficiency, Biochemistry, MESH: DNA Repair, Epigenesis, Genetic, S Phase, MESH: Thymine DNA Glycosylase/genetics, Mice, chemistry.chemical_compound, MESH: Genomic Instability, MESH: DNA-Binding Proteins/genetics, MESH: B-Lymphocytes/metabolism, MESH: Animals, MESH: Cytosine/metabolism, MESH: Epigenesis, Genetic, MESH: Megakaryocyte Progenitor Cells/cytology, MESH: B-Lymphocytes/cytology, B-Lymphocytes, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Cytosine/analogs & derivatives, MESH: S Phase, Base excision repair, DNA-Binding Proteins, MESH: Proto-Oncogene Proteins/genetics, 5-hmC, CpG site, 5-Methylcytosine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Cytosine, Guanine, MESH: Hydroxylation, TDG, Cell cycle, Biology, MESH: DNA-Binding Proteins/metabolism, Hydroxylation, Genomic Instability, Cell Line, Dioxygenases, 03 medical and health sciences, MESH: Tumor Suppressor Protein p53/genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Proto-Oncogene Proteins, Animals, Humans, MESH: Mice, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Megakaryocyte Progenitor Cells, MESH: 5-Methylcytosine/analogs & derivatives, 5-Hydroxymethylcytosine, TET2, MESH: Humans, Base Sequence, MESH: Proto-Oncogene Proteins/metabolism, Mutagenesis, MESH: 5-Methylcytosine/metabolism, Cell Biology, Fibroblasts, Molecular biology, Thymine DNA Glycosylase, MESH: Cell Line, 030104 developmental biology, DNA demethylation, chemistry, DNA glycosylase, MESH: Megakaryocyte Progenitor Cells/metabolism, Tumor Suppressor Protein p53
Abstract

International audience; The family of Ten-Eleven Translocation (TET) proteins is implicated in the process of active DNA demethy-lation and thus in epigenetic regulation. TET 1, 2 and 3 proteins are oxygenases that can hydroxylate 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) and further oxidize 5-hmC into 5-formylcytosine (5-fC) and 5-carboxylcytosine (5-caC). The base excision repair (BER) pathway removes the resulting 5-fC and 5-caC bases paired with a guanine and replaces them with regular cytosine. The question arises whether active modification of 5-mC residues and their subsequent elimination could affect the genomic DNA stability. Here, we generated two inducible cell lines (Ba/F3-EPOR, and UT7) over-expressing wild-type or catalytically inactive human TET2 proteins. Wild-type TET2 induction resulted in an increased level of 5-hmC and a cell cycle defect in S phase associated with higher level of phospho-rylated P53, chromosomal and centrosomal abnormalities. Furthermore, in a thymine-DNA glycosylase (Tdg) deficient context, the TET2-mediated increase of 5-hmC induces mutagenesis characterized by GC > AT transitions in CpG context suggesting a mutagenic potential of 5-hmC metabolites. Altogether, these data suggest that TET2 activity and the levels of 5-hmC and its derivatives should be tightly controlled to avoid genetic and chromosomal instabilities. Moreover, TET2-mediated active demethylation might be a very dangerous process if used to entirely demethylate the genome and might rather be used only at specific loci.

Published
2016
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6. Lymphomyeloid Contribution of an Immune-Restricted Progenitor Emerging Prior to Definitive Hematopoietic Stem Cells

Author

Christina Jensen, Marella F. T. R. de Bruijn, Ewa Sitnicka, Adam J. Mead, Elisa Gomez Perdiguero, Shabnam Kharazi, Qiaolin Deng, Deborah Atkinson, Frederic Geissmann, Luca Melchiori, Anne Hultquist, Iain C. Macaulay, Emanuele Azzoni, Joana Carrelha, Sidinh Luc, Annica Pontén, Joanna C. A. Green, Sten Eirik W. Jacobsen, Isabelle Godin, Tiphaine Bouriez-Jones, Tiago C. Luis, Petter S. Woll, Michael Lutteropp, Rickard Sandberg, Gemma Swiers, Charlotta Böiers, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Böiers, C, Carrelha, J, Lutteropp, M, Luc, S, Green, J, Azzoni, E, Woll, P, Mead, A, Hultquist, A, Swiers, G, Perdiguero, E, Macaulay, I, Melchiori, L, Luis, T, Kharazi, S, Bouriez-Jones, T, Deng, Q, Pontén, A, Atkinson, D, Jensen, C, Sitnicka, E, Geissmann, F, Godin, I, Sandberg, R, de Bruijn, M, and Jacobsen, S

Subjects
Male, Myeloid, Biology, Polymerase Chain Reaction, Mice, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Animals, Myeloid Cells, Lymphocytes, Lymphopoiesis, Myeloid Cell, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Interleukin 3, 0303 health sciences, Innate immune system, Animal, Gene Expression Regulation, Developmental, Hematopoietic Stem Cell, Cell Differentiation, Cell Biology, Hematopoietic Stem Cells, Embryonic stem cell, Endothelial stem cell, Haematopoiesis, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Molecular Medicine, Lymphocyte, Female, Stem cell
Abstract

In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the innate immune system are formed early in development, whereas lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we demonstrate that the embryonic lymphoid commitment process initiates earlier than previously appreciated, prior to emergence of definitive HSCs, through establishment of a previously unrecognized entirely immune-restricted and lymphoid-primed progenitor. Notably, this immune-restricted progenitor appears to first emerge in the yolk sac and contributes physiologically to the establishment of lymphoid and some myeloid components of the immune-system, establishing the lymphomyeloid lineage restriction process as an early and physiologically important lineage-commitment step in mammalian hematopoiesis. Copyright © 2013 Elsevier Inc. All rights reserved.

Published
2013
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7. Apoptotic Topoisomerase I-DNA Complexes Induced by Staurosporine-mediated Oxygen Radicals

Author

Isabelle Plo, Akira Yoshida, Yoshimasa Urasaki, Murat Saparbaev, Smitha Antony, Qasim A. Khan, Glenda Kohlhagen, Yves Pommier, Philippe Pourquier, Eric Solary, Jacques Laval, Olivier Sordet, Pourquier, Philippe, Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et Mecanismes Moleculaires de l'Apoptose, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Stabilité Génétique et Oncogenèse (UMR 8200), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Molecular Pharmacology, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), and National Institutes of Health [Bethesda] (NIH)

Subjects
[SDV]Life Sciences [q-bio], Apoptosis, DNA Fragmentation, Cleavage (embryo), Biochemistry, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, law, Tumor Cells, Cultured, medicine, Humans, Staurosporine, Enzyme Inhibitors, Molecular Biology, 030304 developmental biology, 0303 health sciences, biology, Topoisomerase, Apoptotic DNA fragmentation, DNA, Cell Biology, Cell cycle, Molecular biology, Cell biology, [SDV] Life Sciences [q-bio], DNA Topoisomerases, Type I, chemistry, 030220 oncology & carcinogenesis, biology.protein, Recombinant DNA, DNA supercoil, Reactive Oxygen Species, medicine.drug
Abstract

International audience; Topoisomerase I (Top1), an abundant nuclear enzyme expressed throughout the cell cycle, relaxes DNA supercoiling by forming transient covalent DNA cleavage complexes. We show here that staurosporine, a ubiquitous inducer of apoptosis in mammalian cells, stabilizes cellular Top1 cleavage complexes. These complexes are formed indirectly as staurosporine cannot induce Top1 cleavage complexes in normal DNA with recombinant Top1 or nuclear extract from normal cells. In treated cells, staurosporine produces oxidative DNA lesions and generates reactive oxygen species (ROS). Quenching of these ROS by the antioxidant N-acetyl-l-cysteine or inhibition of the mitochondrial dependent production of ROS by the caspase inhibitor benzyloxycarbonyl-VAD prevents staurosporine-induced Top1 cleavage complexes. Down-regulation of Top1 by small interfering RNA decreases staurosporine-induced apoptotic DNA fragmentation. We propose that Top1 cleavage complexes resulting from oxidative DNA lesions generated by ROS in staurosporine-treated cells contribute to the full apoptotic response.

Published
2004
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