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6,548 results on '"[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]"'

1. Light-independent regulation of algal photoprotection by CO2 availability

Author: M. Águila Ruiz-Sola, Serena Flori, Yizhong Yuan, Gaelle Villain, Emanuel Sanz-Luque, Petra Redekop, Ryutaro Tokutsu, Anika Küken, Angeliki Tsichla, Georgios Kepesidis, Guillaume Allorent, Marius Arend, Fabrizio Iacono, Giovanni Finazzi, Michael Hippler, Zoran Nikoloski, Jun Minagawa, Arthur R. Grossman, Dimitris Petroutsos, Dynamique du protéome et biogenèse du chloroplaste (ChloroGenesis), Physiologie cellulaire et végétale (LPCV), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Light Photosynthesis & Metabolism (Photosynthesis), Department of Plant Biology [Carnegie] (DPB), Carnegie Institution for Science, Universidad de Córdoba = University of Córdoba [Córdoba], National Institute for Basic Biology [Okazaki] (NIBB), Graduate University for Advanced Studies [Hayama] (SOKENDAI), Max Planck Institute of Molecular Plant Physiology (MPI-MP), Max-Planck-Gesellschaft, University of Potsdam = Universität Potsdam, The Human Frontiers Science Program through the funding of the project RGP0046/2018, Prestige Marie-Curie co-financing grant PRESTIGE-2017-1-0028, The International Max Planck Research School 'Primary Metabolism and Plant Growth' at the Max Planck Institute of Molecular Plant Physiology, The program ‘Plan Propio UCO’ from University of Cordoba, The Carnegie Institution for Science and the Department of Energy, DE-SC0019417, The Marie Curie Initial Training Network Accliphot FP7-PEPOPLE-2012-ITN, The Japan Society for the Promotion of Science, JSPS, for the grants-in-Aid for Scientific Research, KAKENHI, 21H04778 and 21H05040, The German Research Foundation DFG HI 739/9.2, ANR-18-CE20-0006,MetaboLIGHT,Regulation de la photosynthèse par la Lumière et le métabolisme chez les algues(2018), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), and European Project: 751039,UNREDE
Subjects: MESH: Chlamydomonas reinhardtii, Multidisciplinary, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Photosystem II Protein Complex, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], General Physics and Astronomy, MESH: Proteins, General Chemistry, MESH: Carbon Dioxide, General Biochemistry, Genetics and Molecular Biology, MESH: Photosynthesis
Abstract: Photosynthetic algae have evolved mechanisms to cope with suboptimal light and CO2 conditions. When light energy exceeds CO2 fixation capacity, Chlamydomonas reinhardtii activates photoprotection, mediated by LHCSR1/3 and PSBS, and the CO2 Concentrating Mechanism (CCM). How light and CO2 signals converge to regulate these processes remains unclear. Here, we show that excess light activates photoprotection- and CCM-related genes by altering intracellular CO2 concentrations and that depletion of CO2 drives these responses, even in total darkness. High CO2 levels, derived from respiration or impaired photosynthetic fixation, repress LHCSR3/CCM genes while stabilizing the LHCSR1 protein. Finally, we show that the CCM regulator CIA5 also regulates photoprotection, controlling LHCSR3 and PSBS transcript accumulation while inhibiting LHCSR1 protein accumulation. This work has allowed us to dissect the effect of CO2 and light on CCM and photoprotection, demonstrating that light often indirectly affects these processes by impacting intracellular CO2 levels.
Published: 2023

2. Multi-Knock—a multi-targeted genome-scale CRISPR toolbox to overcome functional redundancy in plants

Author: Yangjie Hu, Priyanka Patra, Odelia Pisanty, Anat Shafir, Zeinu Mussa Belew, Jenia Binenbaum, Shir Ben Yaakov, Bihai Shi, Laurence Charrier, Gal Hyams, Yuqin Zhang, Maor Trabulsky, Omer Caldararu, Daniela Weiss, Christoph Crocoll, Adi Avni, Teva Vernoux, Markus Geisler, Hussam Hassan Nour-Eldin, Itay Mayrose, Eilon Shani, Tel Aviv University (TAU), University of Copenhagen = Københavns Universitet (UCPH), Reproduction et développement des plantes (RDP), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Fribourg = University of Fribourg (UNIFR)
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Plant Science, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: International audience; Plant genomes are characterized by large and complex gene families that often result in similar and partially overlapping functions 1. This genetic redundancy severely hampers current efforts to uncover novel phenotypes, delaying basic genetic research and breeding programs 2. Here, we describe the development and validation of Multi-Knock, a genome-scale CRISPR toolbox that overcomes functional redundancy in Arabidopsis by simultaneously targeting multiple gene-family members, thus identifying genetically hidden components. We computationally designed 59,129 optimal single guide RNAs (sgRNAs) that each target 2 to 10 genes within a family at once. Furthermore, partitioning the library into ten sub-libraries directed towards a different functional group allows flexible and targeted genetic screens. From the 5,635 sgRNAs targeting the plant transportome, we generated over 3,500 independent Arabidopsis lines that allowed us to identify and characterize the first known cytokinin tonoplast-localized transporters in plants. With the ability to overcome functional redundancy in plants at the genome-scale level, the developed strategy can be readily deployed by scientists and breeders for basic research and to expedite breeding efforts.
Published: 2023

3. Discovery and Enzymatic Screening of Genome-Mined Microbial Levanases to Produce Second-Generation β-(2,6)-Fructooligosaccharides: Catalytic Properties

Author: Lily Chen, Andrea Hill, Jean-Louis Petit, Aline Mariage, Véronique de Berardinis, Salwa Karboune, Department of Food Science and Agricultural Chemistry [Montréal], McGill University = Université McGill [Montréal, Canada], Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-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-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 d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), CFI John R. Evans Leaders N°36708, and The Natural Sciences and Engineering Research Council (NSERC) of Canada
Subjects: [SDV]Life Sciences [q-bio], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Medicine, Biochemistry
Abstract: International audience
Published: 2023

4. Bystander signals from low- and high-dose irradiated human primary fibroblasts and keratinocytes modulate the inflammatory response of peripheral blood mononuclear cells

Author: Isabelle Testard, Elizabeth Garcia-Chartier, Amani Issa, Véronique Collin-Faure, Catherine Aude-Garcia, Serge M Candéias, Protéomique pour la Microbiologie, l'Immunologie et la Toxicologie (PROMIT), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), This work was supported by financing from Electricité de France (EDF) through the Comité de Programme Protection de l’Homme et de l’Environnement (CPPHE), ANR-11-LABX-0063,PRIMES,Physique, Radiobiologie, Imagerie Médicale et Simulation(2011), and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: Radiation, bystander effects (BEs), [SDV]Life Sciences [q-bio], Health, Toxicology and Mutagenesis, gene expressioncytokines, low-dose radiation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.IB.MN]Life Sciences [q-bio]/Bioengineering/Nuclear medicine, cytokines, inflammation, high-dose radiationgene, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.IMM]Life Sciences [q-bio]/Immunology, Radiology, Nuclear Medicine and imaging
Abstract: Irradiated cells can propagate signals to neighboring cells. Manifestations of these so-called bystander effects (BEs) are thought to be relatively more important after exposure to low- vs high-dose radiation and can be mediated via the release of secreted molecules, including inflammatory cytokines, from irradiated cells. Thus, BEs can potentially modify the inflammatory environment of irradiated cells. To determine whether these modifications could affect the functionality of bystander immune cells and their inflammatory response, we analyzed and compared the in vitro response of primary human fibroblasts and keratinocytes to low and high doses of radiation and assessed their ability to modulate the inflammatory activation of peripheral blood mononuclear cells (PBMCs). Only high-dose exposure resulted in either up- or down-regulation of selected inflammatory genes. In conditioned culture media transfer experiments, radiation-induced bystander signals elicited from irradiated fibroblasts and keratinocytes were found to modulate the transcription of inflammatory mediator genes in resting PBMCs, and after activation of PBMCs stimulated with lipopolysaccharide (LPS), a strong inflammatory agent. Radiation-induced BEs induced from skin cells can therefore act as a modifier of the inflammatory response of bystander immune cells and affect their functionality.
Published: 2023

5. FGFR3 Mutational Activation Can Induce Luminal-like Papillary Bladder Tumor Formation and Favors a Male Sex Bias

Author: Ming-Jun Shi, Jacqueline Fontugne, Aura Moreno-Vega, Xiang-Yu Meng, Clarice Groeneveld, Florent Dufour, Aurélie Kamoun, Sia Viborg Lindskrog, Luc Cabel, Clémentine Krucker, Audrey Rapinat, Claire Dunois-Larde, May-Linda Lepage, Elodie Chapeaublanc, Olivier Levrel, Victoria Dixon, Thierry Lebret, Anna Almeida, Aurélien De Reynies, Natacha Rochel, Lars Dyrskjøt, Yves Allory, François Radvanyi, Isabelle Bernard-Pierrot, Bernard-Pierrot, Isabelle, Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ligue Nationale Contre le Cancer (LNCC), Institut Curie [Paris], Hôpital Foch [Suresnes], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: Male, Urology, Urinary Bladder, Sexism, Fibroblast growth factor, Tyrosine kinase receptor, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Luminal tumors, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Mouse model, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], receptor 3, Humans, Animals, Receptor, Fibroblast Growth Factor, Type 3, Estrogen receptor, Sex bias, Bladder cancer, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Fibroblast growth factor receptor 3, Androgen receptor, Urinary Bladder Neoplasms, Tumor microenvironment, Mutation, Androgens, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female
Abstract: Background: Bladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes. Objective: To determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias. Design, setting, and participants: We developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in transgenic mice, with and without carcinogen exposure. Mouse and human BCa transcriptomic data were compared. Intervention: Mutant FGFR3 overexpression in mouse urothelium and siRNA knockdown in cell lines, and N-butyl-N(4-hydroxybutyl)-nitrosamine (BBN) exposure. Outcome measurements and statistical analysis: Impact of transgene dosage on tumor frequency, synergy with BBN treatment, and FGFR3 pathway activation were analyzed. The sex-specific incidence of FGFR3-mutated tumors was evaluated in mice and humans. FGFR3 expression in FGFR3-S249C mouse urothelium and in various human epithelia was measured. Mutant FGFR3 regulation of androgen (AR) and estrogen (ESR1) receptor activity was evaluated, through target gene expression (regulon) and reporter assays. Results and limitations: FGFR3-S249C expression in mice induced low-grade papillary BCa resembling human luminal counterpart at histological, genomic, and transcriptomic levels, and promoted BBN-induced basal BCa formation. Mutant FGFR3 expression levels impacted tumor incidence in mice, and mutant FGFR3–driven human tumors were restricted to epithelia presenting high normal FGFR3 expression levels. BCa male sex bias, also found in our model, was even higher in human FGFR3-mutated tumors compared with wild-type tumors and was associated with higher AR and lower ESR1 regulon activity. Mutant FGFR3 expression inhibited both ESR1 and AR activity in mouse tumors and human cell lines, demonstrating causation only between FGFR3 activation and low ESR1 activity in tumors. Conclusions: Mutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity. Patient summary: By developing a transgenic mouse model, we showed that gain-of-function mutations of FGFR3 receptor, among the most frequent genetic alterations in bladder cancer (BCa), initiate BCa formation. Our results could support noninvasive detection of FGFR3 mutations and FGFR3 targeting in early-stage bladder lesions.
Published: 2023

6. Tuning of Gene Expression in Clostridium phytofermentans Using Synthetic Promoters and CRISPRi

Author: William Rostain, Tom Zaplana, Magali Boutard, Chloé Baum, Sibylle Tabuteau, Mary Sanitha, Mohandass Ramya, Adam Guss, Laurence Ettwiller, Andrew C. Tolonen, Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-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-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 d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Molecular Genetics Laboratory, Department of Genetic Engineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, New England Biolabs, ATIGE 2021 No. 2698, and ANR-16-CE05-0020,Phytocell,Développement des bactéries cellulolytiques Clostridium phytofermentans et Clostridium cellulolyticum comme biocatalyseurs pour la conversion de la biomasse végétale en alcools supérieurs(2016)
Subjects: [SDV]Life Sciences [q-bio], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomedical Engineering, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Medicine, Biochemistry, Genetics and Molecular Biology (miscellaneous)
Abstract: International audience
Published: 2022

7. The 2022 Report on the Human Proteome from the HUPO Human Proteome Project

Author: Gilbert S. Omenn, Lydie Lane, Christopher M. Overall, Charles Pineau, Nicolle H. Packer, Ileana M. Cristea, Cecilia Lindskog, Susan T. Weintraub, Sandra Orchard, Michael H. A. Roehrl, Edouard Nice, Siqi Liu, Nuno Bandeira, Yu-Ju Chen, Tiannan Guo, Ruedi Aebersold, Robert L. Moritz, Eric W. Deutsch, University of Michigan [Ann Arbor], University of Michigan System, Université de Genève = University of Geneva (UNIGE), University of British Columbia [Vancouver], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Macquarie University, Princeton University, University of California [San Diego] (UC San Diego), University of California (UC), Institute for Systems Biology [Seattle] (ISB), G.S.O. acknowledges support from National Institutes of Health Grants P30ES017885-01A1 and U24CA210967, E.W.D. and R.L.M. from National Institutes of Health Grants R01GM087221, R24GM127667, U19AG023122, S10OD026936, and from National Science Foundation Grant DBI-1933311, C.M.O. by Canadian Institutes of Health Research Foundation Grant 148408 and a Canada Research Chair in Protease Proteomics and Systems Biology, N.B. from NIH grant 1R01LM013115, and NSF grant ABI 1759980, M.S.B. by Australian Research Council (CE140100003), C.L. by the Knut and Alice Wallenberg Foundation for the Human Protein Atlas, M.H.R by National Institutes of Health Grants R21 CA263262, U01 CA253217, R21 CA251992, P30 CA008748 (MSKCC CCSG, Pathology Component), NIH-Leidos CPTAC contract 17X173, and Farmer Family Foundation, and and I.M.C. from National Institutes of Health Grant R01GM114141 and Stand Up To Cancer Convergence 3.1416.
Subjects: Mass Spectrometry Interactive Virtual Environment (MassIVE), MESH: Databases, Protein, MESH: Mass Spectrometry, PeptideAtlas, MESH: Humans, chromosome-centric HPP (C-HPP), missing proteins (MP), MESH: Proteomics, General Chemistry, MESH: Open Reading Frames, Biochemistry, Article, Human Protein Atlas, non-MS PE1 proteins, neXtProt protein existence (PE metrics), MESH: Proteome, Human Proteome Project (HPP), Ribo-Seq, uncharacterized protein existence 1 (uPE1), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Grand Challenge Project, Biology and Disease-HPP (B/D-HPP), small open reading frames (smORFs)
Abstract: International audience; The 2022 Metrics of the Human Proteome from the HUPO Human Proteome Project (HPP) illustrates that protein expression has now been credibly detected (neXtProt PE1 level) for 18,407 (93.2%) of the 19,750 predicted proteins coded in the human genome, a net gain of 50 since 2021 from datasets generated around the world and reanalyzed by the HPP. Conversely, the number of neXtProt PE2, PE3, and PE4 missing proteins has been reduced by 78 from 1421 to 1343. This represents continuing experimental progress on the proteome parts list across all the chromosomes, as well as significant reclassifications. Meanwhile, applying proteomics in a vast array of biological and clinical studies continues to yield significant findings and growing integration with other omics platforms. We present highlights from the Chromosome-Centric HPP, Biology and Disease-driven HPP, and HPP Resource Pillars, compare features of mass spectrometry and Olink and Somalogic platforms, note the emergence of translation products from ribosome profiling of small open reading frames, and discuss the launch of the initial HPP Grand Challenge Project, "A Function for Each Protein".
Published: 2022

8. Insight into the control of nodule immunity and senescence during Medicago truncatula symbiosis

Author: Fathi Berrabah, Gautier Bernal, Ait-Salem Elhosseyn, Cyrille El Kassis, Roxane L’Horset, Farouk Benaceur, Jiangqi Wen, Kirankumar S Mysore, Marie Garmier, Benjamin Gourion, Pascal Ratet, Véronique Gruber, Université Amar Telidji - Laghouat, Centre de Recherche en biotechnologie (CRBt) Constantine, Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Peuplements végétaux et bioagresseurs en milieu tropical (UMR PVBMT), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut de Recherche pour le Développement (IRD)-Université de La Réunion (UR)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Oklahoma State University [Stillwater] (OSU), Laboratoire des Interactions Plantes Microbes Environnement (LIPME), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Paris Cite University, Paris Saclay University, National Science Foundation, USA (DBI 0703285 and IOS-1127155), programs for foreign researchers from Paris Cite ́ University and Paris Saclay University, ANR-15-CE20-0005,STAYPINK,Mécanismes contrôlant la transition entre fixation d'azote et sénescence dans les nodosités symbiotiques de légumineuses(2015), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Biology Department, Amar Telidji University, Laghouat, Algeria, Research Unit of Medicinal Plants (RUMP), This work was supported by the grant ANR-15-CE20 0005 (STAYPINK) and funding obtained from the invitation programs for foreign researchers from Paris Cite University and Paris Saclay University. This study contributes to the IdEX Universite de Paris ANR-18-IDEX-0001. Medicago truncatula Tnt1 mutants were created through research funded, in part, by grants from the National Science Foundation, USA (DBI 0703285 and IOS-1127155)., and National Science Foundation, USA (DBI 0703285 and IOS-1127155).
Subjects: Physiology, [SDV]Life Sciences [q-bio], Plant Science, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.GEN.GPL]Life Sciences [q-bio]/Genetics/Plants genetics, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Cysteine Proteases, Nitrogen Fixation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Medicago truncatula, Genetics, Symbiosis, Root Nodules, Plant, Plant Proteins, Sinorhizobium meliloti, [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract: Sequence data from this article can be found in the GenBank/EMBL data libraries under accession numbers: Medtr4g107930: CP3; Medtr4g079770: CP4; Medtr5g022560: CP2; Medtr4g079470: CP5; TC106667: Actine; Medtr1g099310.1: PR8; Medtr4g120970.1/Medtr6g033450.1: PR10; Medtr5g010640.1: PR5.3; Medtr8g096910.1: PR5.6; Medtr5g088770.1: PHYTOCYSTATIN32; Medtr2g026040.1: PHYTOCYSTATIN5; Medtr4g085800: DNF2; Medtr3g079850: SymCRK; MtrunA17_Chr7g0239441: RSD. Sequence data from this article can be found in the GenBank/EMBL data libraries under accession numbers: Medtr4g107930: CP3; Medtr4g079770: CP4; Medtr5g022560: CP2; Medtr4g079470: CP5; TC106667: Actine; Medtr1g099310.1: PR8; Medtr4g120970.1/Medtr6g033450.1: PR10; Medtr5g010640.1: PR5.3; Medtr8g096910.1: PR5.6; Medtr5g088770.1: PHYTOCYSTATIN32; Medtr2g026040.1: PHYTOCYSTATIN5; Medtr4g085800: DNF2; Medtr3g079850: SymCRK; MtrunA17_Chr7g0239441: RSD.; International audience; Medicago (Medicago truncatula) establishes a symbiosis with the rhizobia Sinorhizobium sp, resulting in the formation of nodules where the bacteria fix atmospheric nitrogen. The loss of immunity repression or early senescence activation compromises symbiont survival and leads to the formation of nonfunctional nodules (fix−). Despite many studies exploring an overlap between immunity and senescence responses outside the nodule context, the relationship between these processes in the nodule remains poorly understood. To investigate this phenomenon, we selected and characterized three Medicago mutants developing fix− nodules and showing senescence responses. Analysis of specific defense (PATHOGENESIS-RELATED PROTEIN) or senescence (CYSTEINE PROTEASE) marker expression demonstrated that senescence and immunity seem to be antagonistic in fix− nodules. The growth of senescence mutants on non-sterile (sand/perlite) substrate instead of sterile in vitro conditions decreased nodule senescence and enhanced defense, indicating that environment can affect the immunity/senescence balance. The application of wounding stress on wild-type (WT) fix+ nodules led to the death of intracellular rhizobia and associated with co-stimulation of defense and senescence markers, indicating that in fix+ nodules the relationship between the two processes switches from opposite to synergistic to control symbiont survival during response to the stress. Our data show that the immune response in stressed WT nodules is linked to the repression of DEFECTIVE IN NITROGEN FIXATION 2 (DNF2), Symbiotic CYSTEINE-RICH RECEPTOR-LIKE KINASE (SymCRK), and REGULATOR OF SYMBIOSOME DIFFERENTIATION (RSD), key genes involved in symbiotic immunity suppression. This study provides insight to understand the links between senescence and immunity in Medicago nodules. Analyses of Medicago mutants with non-functional nodules highlight the relationship and mechanisms controlling the establishment of the immune and senescence programs during nodule organogenesis.
Published: 2022

9. Development of versatile allele-specific siRNAs able to silence all the dominant dynamin 2 mutations

Author: Swati Dudhal, Lylia Mekzine, Bernard Prudhon, Karishma Soocheta, Bruno Cadot, Kamel Mamchaoui, Delphine Trochet, Marc Bitoun, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Bitoun, Marc
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, allele-specific silencing, MT: RNA/DNA Editing, migration, gene therapy, dominant centronuclear myopathy, adhesion, dynamin 2, RNA interference, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Discovery, endocytosis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Dominant centronuclear myopathy (CNM) is a rare form of congenital myopathy associated with a wide clinical spectrum, from severe neonatal to milder adult forms. There is no available treatment for this disease due to heterozygous mutations in the DNM2 gene encoding Dynamin 2 (DNM2). Dominant DNM2 mutations also cause rare forms of Charcot-Marie-Tooth disease and hereditary spastic paraplegia, and deleterious DNM2 overexpression was noticed in several diseases. The proof of concept for therapy by allele-specific RNA interference devoted to silence the mutated mRNA without affecting the normal allele was previously achieved in a mouse model and patient-derived cells, both expressing the most frequent DNM2 mutation in CNM. In order to have versatile small interfering RNAs (siRNAs) usable regardless of the mutation, we have developed allele-specific siRNAs against two non-pathogenic single-nucleotide polymorphisms (SNPs) frequently heterozygous in the population. In addition, allele-specific siRNAs against the p.S619L DNM2 mutation, a mutation frequently associated with severe neonatal cases, were developed. The beneficial effects of these new siRNAs are reported for a panel of defects occurring in patient-derived cell lines. The development of these new molecules allows targeting the large majority of the patients harboring DNM2 mutations or overexpression by only a few siRNAs.
Published: 2022

10. G4access identifies G-quadruplexes and their associations with open chromatin and imprinting control regions

Author: Esnault, Cyril, Magat, Talha, Zine El Aabidine, Amal, Garcia-Oliver, Encar, Cucchiarini, Anne, Bouchouika, Soumya, Lleres, David, Goerke, Lutz, Luo, Yu, Verga, Daniela, Lacroix, Laurent, Feil, Robert, Spicuglia, Salvatore, Mergny, Jean‐louis, Andrau, Jean-Christophe, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Laboratoire d'Optique et Biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'Ecole Normale Supérieure (IBENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Université - Faculté des Sciences (AMU SCI), Aix Marseille Université (AMU), and ANR-20-CE12-0023,G4Access,Role des G-quadruplexes dans la régulation transcriptionnelle(2020)
Subjects: [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, G-quadruplex, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], transcription
Abstract: International audience; Metazoan promoters are enriched in secondary DNA structure-forming motifs, such as G-quadruplexes (G4s). Here we describe ‘G4access’, an approach to isolate and sequence G4s associated with open chromatin via nuclease digestion. G4access is antibody- and crosslinking-independent and enriches for computationally predicted G4s (pG4s), most of which are confirmed in vitro. Using G4access in human and mouse cells, we identify cell-type-specific G4 enrichment correlated with nucleosome exclusion and promoter transcription. G4access allows measurement of variations in G4 repertoire usage following G4 ligand treatment, HDAC and G4 helicases inhibitors. Applying G4access to cells from reciprocal hybrid mouse crosses suggests a role for G4s in the control of active imprinting regions. Consistently, we also observed that G4access peaks are unmethylated, while methylation at pG4s correlates with nucleosome repositioning on DNA. Overall, our study provides a new tool for studying G4s in cellular dynamics and highlights their association with open chromatin, transcription and their antagonism to DNA methylation.
Published: 2023

11. Phenotypic effects of genetic variants associated with autism

Author: Rolland, Thomas, Cliquet, Freddy, Anney, Richard, Moreau, Clara, Traut, Nicolas, Mathieu, Alexandre, Huguet, Guillaume, Duan, Jinjie, Warrier, Varun, Portalier, Swan, Dry, Louise, Leblond, Claire, Douard, Elise, Amsellem, Frédérique, Malesys, Simon, Maruani, Anna, Toro, Roberto, Børglum, Anders D., Grove, Jakob, Baron-Cohen, Simon, Packer, Alan, Chung, Wendy, Jacquemont, Sébastien, Delorme, Richard, Bourgeron, Thomas, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cardiff University, Centre de Recherches Interdisciplinaires (CRI), Université Paris Cité (UPCité), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University [Aarhus], Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), University of Cambridge [UK] (CAM), Université de Montréal (UdeM), Service psychiatrique de l'enfant et de l'adolescent [CHU Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Simons Foundation, Columbia University Medical Center (CUMC), Columbia University [New York], S.J. is supported by Calcul Quebec and Compute Canada, NIH U01 grant for CAMP (1U01MH119690–01), the Canadian Institutes of Health Research, CIHR_400528, and the Institute of Data Valorization (IVADO) through the Canada First Research Excellence Fund. S.J. is a recipient of a Canada Research Chair in neurodevelopmental disorders and a chair from the Jeanne et Jean Louis Levesque Foundation. This work was funded by Institut Pasteur, the Bettencourt-Schueller Foundation, Université de Paris, the Conny-Maeva Charitable Foundation, the Cognacq Jay Foundation, the Eranet-Neuron (ALTRUISM) and the GenMed Labex, AIMS-2-TRIALS, which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777394 and the Inception program (Investissement d’Avenir grant ANR-16-CONV-0005). This project has received funding from the Horizon Europe programs CANDY and R2D2-MH under grant agreement nos. 847818 and 101057385. Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. Additionally, for UK partners, the work was funded by UK Research and Innovation under the UK government’s Horizon Europe funding guarantee (grant no.10039383). The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003) and the Universities and University Hospitals of Aarhus and Copenhagen. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). S.B.C. received funding from the Wellcome Trust 214322\Z\18\Z, support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. S.B.C. also received funding from the Autism Centre of Excellence, SFARI, the Templeton World Charitable Fund, the Medical Research Council and the National Institute for Health Research Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research Applied Research Collaboration East of England., ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and European Project: 777394,H2020-JTI-IMI2-2016-10-two-stage,AIMS-2-TRIALS(2018)
Subjects: [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: International audience; While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants.
Published: 2023

12. Modification de l'organisation tridimensionnelle de la chromatine par l'oncogène Tax de HTLV-1 : conséquences fonctionnelles sur la transcription et l'épissage alternatif des gènes cellulaires

Author: Marie, Paul, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1, and Franck Mortreux
Subjects: organisation du génome, alternative splicing, HTLV-1, Chromosome conformation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], épissage alternatif, transcription, Genome organization
Abstract: The NF-κB pathway controls the transcription of numerous genes involved in major physiological processes such as inflammation and immune response. However, its chronic activation is frequently associated with diseases such as cancer. The 3D organization of chromatin plays a role in coordinating transcriptional regulations established during NF-κB pathway activation. My work demonstrates that, in the context of NF-κB pathway activation by the HTLV-1 retrovirus oncoprotein Tax, numerous alternative splicing deregulations are mediated by the intragenic recruitment of the NF-κB p65/RelA factor near regulated exons through its interaction capabilities with splicing factors, including the RNA helicase DDX17. Using Hi-C, 4C, and 3C approaches, my data reveal that transcriptional and post-transcriptional regulations induced by Tax, particularly through the NF-κB pathway, are accompanied by a reorganization of the 3D genome architecture, leading to the formation of multigenic complexes composed of genes regulated by Tax at the transcriptional level or at the alternative splicing. Analyses of p65/RelA chromatin occupancy, as well as molecular approaches to experimentally modulate p65/RelA recruitment to the chromatin, have identified that intragenic binding of p65/RelA contributes to the formation of contacts between genes and their regulation at the transcriptional and alternative splicing levels. These findings provide new insight into the complex regulatory mechanisms involved in gene perturbations upon HTLV-1 infection as well as in pathologies associated with chronic NF-κB activation.; L’activation de la voie NF-κB contrôle la transcription de nombreux gènes engagés dans des processus physiologiques majeurs tels que l’inflammation et la réponse immune. Néanmoins, son activation chronique est fréquemment associée dans des maladies tels que les cancers. L’organisation tridimensionnelle de la chromatine joue un rôle dans la coordination des régulations transcriptionnelles mise en place lors de l’activation de la voie NF-κB. Mes travaux montrent dans un contexte d’activation de la voie NF-κB par l’oncogène Tax du rétrovirus HTLV-1 que de nombreuses dérégulations d’épissage alternatif sont médiées par le recrutement intragénique du facteur NF-κB p65/RelA à proximité des exons régulés via ses capacité d’interaction avec des facteurs d’épissage, dont l’hélicase à ARN DDX17. Par des approches de Hi-C, 4C et 3C, mes données montrent que les régulations transcriptionnelles et co-transcriptionnelles engendrées par Tax, notamment via l’activation de la voie NF-κB, s’accompagnent d’une réorganisation de l’architecture tridimensionnelle du génome, induisant la formation de complexes multigéniques composés de gènes régulés par Tax dans leur niveau transcriptionnel ou leur épissage alternatif. Les analyses de l’enrichissement à la chromatine de p65/RelA, ainsi que des approches moléculaires permettant de moduler expérimentalement le recrutement de p65/RelA à la chromatine, ont permis d’identifier que la fixation intragénique de p65/RelA participe à la formation de contacts entre gènes et à leurs régulations au niveau de la transcription et de l’épissage alternatif. Ces données apportent de nouvelles connaissances dans les mécanismes de régulation lors de l’infection par HTLV-1 mais également dans les pathologies associées à l’activation de la voie NF-κB.
Published: 2023

13. Short tandem repeats are important contributors to silencer elements in T cells

Author: Saadat Hussain, Nori Sadouni, Dominic van Essen, Lan T M Dao, Quentin Ferré, Guillaume Charbonnier, Magali Torres, Frederic Gallardo, Charles-Henri Lecellier, Tom Sexton, Simona Saccani, Salvatore Spicuglia, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics
Abstract: The action of cis-regulatory elements with either activation or repression functions underpins the precise regulation of gene expression during normal development and cell differentiation. Gene activation by the combined activities of promoters and distal enhancers has been extensively studied in normal and pathological contexts. In sharp contrast, gene repression by cis-acting silencers, defined as genetic elements that negatively regulate gene transcription in a position-independent fashion, is less well understood. Here, we repurpose the STARR-seq approach as a novel high-throughput reporter strategy to quantitatively assess silencer activity in mammals. We assessed silencer activity from DNase hypersensitive I sites in a mouse T cell line. Identified silencers were associated with either repressive or active chromatin marks and enriched for binding motifs of known transcriptional repressors. CRISPR-mediated genomic deletions validated the repressive function of distinct silencers involved in the repression of non-T cell genes and genes regulated during T cell differentiation. Finally, we unravel an association of silencer activity with short tandem repeats, highlighting the role of repetitive elements in silencer activity. Our results provide a general strategy for genome-wide identification and characterization of silencer elements.
Published: 2023

14. Glutaredoxin regulation of primary root growth confers early drought stress tolerance in pearl millet

Author: Carla de la Fuente, Alexandre Grondin, Bassirou Sine, Marilyne Debieu, Christophe Belin, Amir Hajjarpoor, Jonathan A. Atkinson, Sixtine Passot, Marine Salson, Julie Orjuela, Christine Tranchant-Dubreuil, Jean-Rémy Brossier, Maxime Steffen, Charlotte Morgado, Hang Ngan Dinh, Bipin K. Pandey, Julie Darmau, Antony Champion, Anne- Sophie Petitot, Celia Barrachina, Marine Pratlong, Thibault Mounier, Pascal Gantet, Prakash Gangashetty, Yann Guédon, Vincent Vadez, Jean-Philippe Reichheld, Malcolm J. Bennett, Ndjido Kane, Soazig Guyomarc’h, Darren M. Wells, Yves Vigouroux, Laurent Laplaze, Diversité, adaptation, développement des plantes (UMR DIADE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), LMI Adaptation des Plantes et microorganismes associés aux Stress Environnementaux [Dakar] (LAPSE), Institut de Recherche pour le Développement (IRD), Centre d'Etude Regional Pour l'Amelioration de l'Adaptation A la Secheresse (CERAAS), Institut Sénégalais de Recherches Agricoles [Dakar] (ISRA), Laboratoire Génome et développement des plantes (LGDP), Université de Perpignan Via Domitia (UPVD)-Centre National de la Recherche Scientifique (CNRS), University of Nottingham, UK (UON), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), International Crops Research Institute for the Semi-Arid Tropics [Inde] (ICRISAT), Consultative Group on International Agricultural Research [CGIAR] (CGIAR), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Montpellier, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Montpellier (UM), Agropolis Fondation (NewPearl grant n° AF 1301-015 in the frame of the CERES initiative, ValoRoot grant n°2202-002, and Flagship Project CalClim grant no. 1802-002)Fondazione Cariplo (n° FC 2013-0891)- CGIAR Research Programme on Grain Legumes and Dryland Cereals (GLDC), ANR-17-CE20-0022,RootAdapt,Traits racinaires pour l'adaptation du mil au climat futur en Afrique de l'Ouest(2017), ANR-10-LABX-0001,AGRO,Agricultural Sciences for sustainable Development(2010), ANR-16-IDEX-0006,MUSE,MUSE(2016), and European Project
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics
Abstract: Seedling root traits impact plant establishment under challenging environments. Pearl millet is one of the most heat and drought tolerant cereal crops that provides a vital food source across the sub-Saharan Sahel region. Pearl millet’s early root system features a single fast-growing primary root which we hypothesize is an adaptation to the Sahelian climate. Using crop modelling, we demonstrate that early drought stress is an important constraint in agrosystems in the Sahel where pearl millet was domesticated. Furthermore, we show that increased pearl millet primary root growth is correlated with increased early water stress tolerance in field conditions. Genetics including GWAS and QTL approaches identify genomic regions controlling this key root trait. Combining gene expression data, re-sequencing and re- annotation of one of these genomic regions identified a glutaredoxin-encoding genePgGRXC9as the candidate stress resilience root growth regulator. Functional characterization of its closest Arabidopsis homologAtROXY19revealed a novel role for this glutaredoxin (GRX) gene clade in regulating cell elongation. In summary, our study suggests a conserved function for GRX genes in conferring root cell elongation and enhancing resilience of pearl millet to its Sahelian environment.
Published: 2023

15. PARTICLE SHAPE AND INTRINSIC CELLULAR VARIABILITY SHAPE THE RESPONSES OF MACROPHAGES TO POLYSTYRENE NANO AND MICRO PARTICLES

Author: Collin-Faure, Véronique, Dalzon, Bastien, Torres, Anaelle, Rabilloud, Thierry, Protéomique pour la Microbiologie, l'Immunologie et la Toxicologie (PROMIT), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: [CHIM.POLY]Chemical Sciences/Polymers, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: International audience; Nanoparticles and among them nanoplastics are generally considered to induce more biological effects than bigger particles because of their greater penetration in bodies and cells. Nevertheless, it is known that particles up to a few microns can translocate through the epithelial barriers and be transported to distal organs. As the particles surface and mass increase with the square and the cube of the size, it may be anticipated that microparticles may induce stronger effects than smaller ones, especially when their size begins to approach the size of the cells. To investigate this hypothesis, we exposed macrophages (i.e. cells that are able to scavenge particles over a wide size range) to polystyrene particles of 0.1, 1 and 10 µm in diameter, and analyzed their responses by a proteomic approach. This analysis showed an important common core response for the three particles sizes, but also that larger particles induced a more important response than smaller ones at equal mass concentration. As this suggested a role of the internalized plastic mass in the response, we also investigated an often-overlooked parameter, i.e. the heterogeneity of the cells in their propensity to internalize (plastic) particles. We showed that macrophages vary greatly in their ability to internalize plastic particles. Quite interestingly, “the appetite came with the eating”, so that the final population of cells exposed to a single concentration of plastic particles is indeed a mix of cells with very different loads of internalized plastics. Unsurprisingly, heavily-loaded cells show stronger responses than lightly-loaded cells. We also showed that plastic particles persist in macrophages.When brought together, these data draw a picture where the maintenance of the function of the immune system is assured by the lightly-loaded cells, while the heavily-loaded cells may induce local effects. This balance may change over time in case of continuous exposure, because of particle accumulation.
Published: 2023

16. Can Omics Biology Go Subjective because of Artificial Intelligence? A Comment on 'Challenges and Opportunities for Bayesian Statistics in Proteomics' by Crook et al

Author: Thomas Burger, Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), ANR-19-P3IA-0003,MIAI,MIAI @ Grenoble Alpes(2019), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Burger, Thomas, MIAI @ Grenoble Alpes - - MIAI2019 - ANR-19-P3IA-0003 - P3IA - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID
Subjects: Proteomics, Proteome, Artificial Intelligence, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Computational Biology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Bayes Theorem, General Chemistry, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Biochemistry, ComputingMilieux_MISCELLANEOUS, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract: In their recent review (
Published: 2022

17. Fluorescence Detection of the Persistent Organic Pollutant Chlordecone in Water at Environmental Concentrations

Author: Oriane Della‐Negra, Aya Esther Kouassi, Jean‐Pierre Dutasta, Pierre‐Loïc Saaidi, Alexandre Martinez, Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie - UMR5182 (LC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-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-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 d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), and Préfecture de Martinique, Plan Chlordécone III, action remediation (2019).
Subjects: [SDV]Life Sciences [q-bio], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Organic Chemistry, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Chemistry, Catalysis
Published: 2023

18. Genomic changes during the evolution of the Coxiella genus along the parasitism-mutualism continuum

Author: Santos-Garcia, Diego, Morel, Olivier, Henri, Hélène, El Filali, Adil, Buysse, Marie, Noël, Valérie, Mccoy, Karen, Gottlieb, Yuval, Klasson, Lisa, Zenner, Lionel, Duron, Olivier, Vavre, Fabrice, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Koret School of Veterinary Medicine, The Hebrew University of Jerusalem (HUJ)-The Robert H. Smith faculty of Agriculture, Food and Environment, and Uppsala Universitet [Uppsala]
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: International audience; The Coxiellaceae family is composed of five genera showing lifestyles ranging from free-living to symbiosis. Among them, Coxiella burnetii is a well-known pathogen causing Q fever in humans. This bacterium presents both intracellular (parasitic) and environmental (resistant) forms. Recently, several environmental Coxiella genomes have been reported, among which several have come from intracellular mutualistic symbionts of ticks, termed Coxiella-like endosymbionts. We sequenced two new Coxiella-LE genomes from Dermacentor marginatus (CLEDm) and Ornithodoros maritimus (CLEOmar) ticks, the latter belonging to the C. burnetii lineage. Using these newly sequenced Coxiella-LEs and 43 Coxiellaceae genomes, we conducted comparative genomic and phylogenomic analyses to increase our knowledge of C. burnetii pathogenicity and the emergence of Coxiella-LEs. Results highlight the probably parasitic nature of the common ancestor of the Coxiellaceae. Indeed, the virulence factor Dot/Icm T4 Secretion System is present in most, but not all, Coxiellaceae. Whereas it is part of a putative pathogenic island in C. burnetii, it has been entirely lost or inactivated in Coxiella-LEs, suggesting its importance in pathogenesis. Additionally, we found that a Sha/Mrp antiporter was laterally acquired in the C. burnetii lineage. This antiporter might be involved in alkali resistance and the development of the resistant form that is able to persist in the environment for long periods of time. The Sha operon is eroded or absent in Coxiella-LEs. Finally, we found that all Coxiella representatives produce B vitamins and co-factors indicating a pre-adaptation of Coxiella to mutualism with hematophagous arthropods. Accordingly, the ancestor of C. burnetii and Coxiella-LEs was likely a parasitic bacterium able to manipulate its host cell and to produce vitamins and co-factors for its own use.
Published: 2023

19. Genes Involved in miRNA Biogenesis Are Not Downregulated in SARS-CoV-2 Infection

Author: Nathalie Garnier, Famara Sane, Layal Massara, Fabrice Soncin, Philippe Gosset, Didier Hober, Sabine Szunerits, Ilka Engelmann, Pathogenèse virale du diabète de type 1 - ULR 3610 (Laboratoire de Virologie), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut d’Électronique, de Microélectronique et de Nanotechnologie - UMR 8520 (IEMN), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), CHU Lille, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Laboratory for Integrated Micro Mechatronics Systems (LIMMS), The University of Tokyo (UTokyo)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, NanoBioInterfaces - IEMN (NBI - IEMN), Université catholique de Lille (UCL)-Université catholique de Lille (UCL)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF)-JUNIA (JUNIA), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier]-Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), This research was supported by I-SITE ULNE, the Centre Hospitalier Universitaire de Lilleand Université de Lille. N.G. wants to thank the Ecole Doctorale Biologie-Santé for a PhD fellowship., and ANR-16-IDEX-0004,ULNE,ULNE(2016)
Subjects: [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Ago2, SARS-CoV-2, Exportin-5, COVID-19, Drosha, DGCR8, Infectious Diseases, RNA interference, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, miRNA, Dicer
Abstract: International audience; miRNAs, small non-coding RNAs that regulate gene expression, are involved in various pathological processes, including viral infections. Virus infections may interfere with the miRNA pathway through the inhibition of genes involved in miRNA biogenesis. A reduction in the number and the levels of miRNAs expressed in nasopharyngeal swabs of patients with severe COVID-19 was lately observed by us, pointing towards the potential of miRNAs as possible diagnostic or prognostic biomarkers for predicting outcomes among patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The objective of the present study was to investigate whether SARS-CoV-2 infection influences the expression levels of messenger RNAs (mRNAs) of key genes involved in miRNA biogenesis. mRNA levels of AGO2, DICER1, DGCR8, DROSHA, and Exportin-5 (XPO5) were measured by quantitative reverse-transcription polymerase chain reaction (RT-qPCR) in nasopharyngeal swab specimens from patients with COVID-19 and controls, as well as in cells infected with SARS-CoV-2 in vitro. Our data showed that the mRNA expression levels of AGO2, DICER1, DGCR8, DROSHA, and XPO5 were not significantly different in patients with severe COVID-19 when compared to patients with non-severe COVID-19 and controls. Similarly, the mRNA expression of these genes was not affected by SARS-CoV-2 infection in NHBE and Calu-3 cells. However, in Vero E6 cells, AGO2, DICER1, DGCR8, and XPO5 mRNA levels were slightly upregulated 24 h after infection with SARS-CoV-2. In conclusion, we did not find evidence for downregulation of mRNA levels of miRNA biogenesis genes during SARS-CoV-2 infection, neither ex vivo nor in vitro.
Published: 2023

20. Differential Effects of Overexpression of Wild Type and Kinase-Dead MELK in Fibroblasts and Keratinocytes, Potential Implications for Skin Wound Healing and Cancer

Author: Łukasz Szymański, Krystyna Lieto, Robert Zdanowski, Sławomir Lewicki, Jean-Pierre Tassan, Jacek Z. Kubiak, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Military Institute of Medicine, Warsaw, Kazimierz Pulaski University of Technology and Humanities in Radom, Institut de Génétique et Développement de Rennes (IGDR), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: AKT1, keratinocytes, p53, proliferation, Organic Chemistry, MAPK9, p38, wound healing, General Medicine, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], MAPK, Catalysis, Computer Science Applications, Inorganic Chemistry, ERK, fibroblasts, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MELK, JNK, cell cycle, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract: International audience; Maternal embryonic leucine-zipper kinase (MELK) plays a significant role in cell cycle progression, mitosis, cell migration, cell renewal, gene expression, embryogenesis, proliferation, apoptosis, and spliceosome assembly. In addition, MELK is known to be overexpressed in multiple types of cancer and is associated with cancer proliferation. Tumorigenesis shares many similarities with wound healing, in which the rate of cell proliferation is a critical factor. Therefore, this study aimed to determine the involvement of MELK in the regulation of cell division in two cell types involved in this process, namely fibroblasts and keratinocytes. We examined how temporal overexpression of wild-type and kinase-dead MELK kinase variants affect the rate of proliferation, viability, cell cycle, and phosphorylation state of other kinases involved in these processes, such as ERK1/2, AKT1, MAPK9, p38, and p53. We explored if MELK could be used as a therapeutic stimulator of accelerated wound healing via increased proliferation. We observed that aberrant expression of MELK results in abnormal proliferation, altered cell cycle distribution, and decreased viability of the cells, which challenge the utility of MELK in accelerated wound healing. Our results indicate that, at least in healthy cells, any deviation from precisely controlled MELK expression is harmful to fibroblasts and keratinocytes.
Published: 2023
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21. Nkx2-5 Loss of Function in the His-Purkinje System Hampers Its Maturation and Leads to Mechanical Dysfunction

Author: Caroline Choquet, Pierre Sicard, Juliette Vahdat, Thi Hong Minh Nguyen, Frank Kober, Isabelle Varlet, Monique Bernard, Sylvain Richard, Robert G. Kelly, Nathalie Lalevée, Lucile Miquerol, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Transcriptomique et génomique appliquée - Transcriptomics and Applied Genomics (TAG), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Hanoi University of Science and Technology (HUST), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: RSR’ complex, cell dropout, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], His-Purkinje system, fast conduction markers, Cx40, strain defects, cardiac dyssynchrony, Pharmacology (medical), General Pharmacology, Toxicology and Pharmaceutics, [SDV.BDD]Life Sciences [q-bio]/Development Biology
Abstract: International audience; The ventricular conduction or His-Purkinje system (VCS) mediates the rapid propagation and precise delivery of electrical activity essential for the synchronization of heartbeats. Mutations in the transcription factor Nkx2-5 have been implicated in a high prevalence of developing ventricular conduction defects or arrhythmias with age. Nkx2-5 heterozygous mutant mice reproduce human phenotypes associated with a hypoplastic His-Purkinje system resulting from defective patterning of the Purkinje fiber network during development. Here, we investigated the role of Nkx2-5 in the mature VCS and the consequences of its loss on cardiac function. Neonatal deletion of Nkx2-5 in the VCS using a Cx40-CreERT2 mouse line provoked apical hypoplasia and maturation defects of the Purkinje fiber network. Genetic tracing analysis demonstrated that neonatal Cx40-positive cells fail to maintain a conductive phenotype after Nkx2-5 deletion. Moreover, we observed a progressive loss of expression of fast-conduction markers in persistent Purkinje fibers. Consequently, Nkx2-5-deleted mice developed conduction defects with progressively reduced QRS amplitude and RSR’ complex associated with higher duration. Cardiac function recorded by MRI revealed a reduction in the ejection fraction in the absence of morphological changes. With age, these mice develop a ventricular diastolic dysfunction associated with dyssynchrony and wall-motion abnormalities without indication of fibrosis. These results highlight the requirement of postnatal expression of Nkx2-5 in the maturation and maintenance of a functional Purkinje fiber network to preserve contraction synchrony and cardiac function.
Published: 2023
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22. Single-cell transcriptional uncertainty landscape of cell differentiation

Author: Nan Papili Gao, Olivier Gandrillon, András Páldi, Ulysse Herbach, Rudiyanto Gunawan, Institute for Chemical and Bioengineering [ETH Zürich] (ICB), Department of Chemistry and Applied Biosciences [ETH Zürich] (D-CHAB), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modélisation multi-échelle des dynamiques cellulaires : application à l'hématopoïese (DRACULA), Institut Camille Jordan (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), 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)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-Inria Lyon, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Biology, genetics and statistics (BIGS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY), and ANR-17-CE12-0031,SinCity,Analyses transcriptomiques sur cellules uniques dont la généalogie est identifiée au cours d'un processus de différentiation(2017)
Subjects: RNA velocity, cell differentiation, General Immunology and Microbiology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], gene expression, General Medicine, transcriptional uncertainty, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], General Pharmacology, Toxicology and Pharmaceutics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], General Biochemistry, Genetics and Molecular Biology, single cell
Abstract: Background: Single-cell studies have demonstrated the presence of significant cell-to-cell heterogeneity in gene expression. Whether such heterogeneity is only a bystander or has a functional role in the cell differentiation process is still hotly debated. Methods: In this study, we quantified and followed single-cell transcriptional uncertainty – a measure of gene transcriptional stochasticity in single cells – in 10 cell differentiation systems of varying cell lineage progressions, from single to multi-branching trajectories, using the stochastic two-state gene transcription model. Results: By visualizing the transcriptional uncertainty as a landscape over a two-dimensional representation of the single-cell gene expression data, we observed universal features in the cell differentiation trajectories that include: (i) a peak in single-cell uncertainty during transition states, and in systems with bifurcating differentiation trajectories, each branching point represents a state of high transcriptional uncertainty; (ii) a positive correlation of transcriptional uncertainty with transcriptional burst size and frequency; (iii) an increase in RNA velocity preceding the increase in the cell transcriptional uncertainty. Conclusions: Our findings suggest a possible universal mechanism during the cell differentiation process, in which stem cells engage stochastic exploratory dynamics of gene expression at the start of the cell differentiation by increasing gene transcriptional bursts, and disengage such dynamics once cells have decided on a particular terminal cell identity. Notably, the peak of single-cell transcriptional uncertainty signifies the decision-making point in the cell differentiation process.
Published: 2023

23. Analysis of the P. lividus sea urchin genome highlights contrasting trends of genomic and regulatory evolution in deuterostomes

Author: Ferdinand Marlétaz, Arnaud Couloux, Julie Poulain, Karine Labadie, Corinne Da Silva, Sophie Mangenot, Benjamin Noel, Albert J. Poustka, Philippe Dru, Cinta Pegueroles, Marco Borra, Elijah K. Lowe, Guy Lhomond, Lydia Besnardeau, Stéphanie Le Gras, Tao Ye, Daria Gavriouchkina, Roberta Russo, Caterina Costa, Francesca Zito, Letizia Anello, Aldo Nicosia, Maria Antonietta Ragusa, Marta Pascual, M. Dolores Molina, Aline Chessel, Marta Di Carlo, Xavier Turon, Richard R. Copley, Jean-Yves Exposito, Pedro Martinez, Vincenzo Cavalieri, Smadar Ben Tabou de Leon, Jenifer Croce, Paola Oliveri, Valeria Matranga, Maria Di Bernardo, Julia Morales, Patrick Cormier, Anne-Marie Geneviève, Jean Marc Aury, Valérie Barbe, Patrick Wincker, Maria Ina Arnone, Christian Gache, Thierry Lepage, Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-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), Laboratoire de Biologie du Développement de Villefranche sur mer (LBDV), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de la Mer de Villefranche (IMEV), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), LBDV_EVOINSIDE (EvoInside), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de la Mer de Villefranche (IMEV), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (IBV), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Biologie intégrative des organismes marins (BIOM), and Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Observatoire océanologique de Banyuls (OOB)
Subjects: [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Eriçons de mar, Genòmica, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Epigenetics, Genomics, Gene expression, Epigenètica, Biochemistry, Genetics and Molecular Biology (miscellaneous), Expressió gènica, Sea urchins, Article
Abstract: International audience; Sea urchins are emblematic models in developmental biology and display several characteristics that set them apart from other deuterostomes. To uncover the genomic cues that may underlie these specificities, we generated a chromosome-scale genome assembly for the sea urchin Paracentrotus lividus and an extensive gene expression and epigenetic profiles of its embryonic development. We found that, unlike vertebrates, sea urchins retained ancestral chromosomal linkages but underwent very fast intrachromosomal gene order mixing. We identified a burst of gene duplication in the echinoid lineage and showed that some of these expanded genes have been recruited in novel structures (water vascular system, Aristotle’s lantern, and skeletogenic micromere lineage). Finally, we identified gene-regulatory modules conserved between sea urchins and chordates. Our results suggest that gene-regulatory networks controlling development can be conserved despite extensive gene order rearrangement.
Published: 2023

24. Population Genomic Evidence of Adaptive Response during the Invasion History of Plasmodium falciparum in the Americas

Author: Margaux J M Lefebvre, Josquin Daron, Eric Legrand, Michael C Fontaine, Virginie Rougeron, Franck Prugnolle, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Biologie de Plasmodium et Vaccins - Malaria Parasite Biology and Vaccines, Institut Pasteur [Paris] (IP), Groningen Institute for Evolutionary Life Sciences [Groningen] (GELIFES), University of Groningen [Groningen], Reconciling Ecological and Human Adaptations for Biosphere Sustainability (REHABS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Nelson Mandela University [Port Elizabeth], This work was supported by the French ANR MICETRAL (ANR-19-CE35-0010) and ANR GENAD (ANR-20-CE35-003)., ANR-19-CE35-0010,MICETRAL,Souris envahissantes et malaria de rongeur: analyse d'un saut d'hôte naturel impliquant deux modèles de laboratoire très étudiés(2019), ANR-20-CE35-0003,GENAD,Adaptation génétique et histoire évolutive de Plasmodium vivax en Amérique Genetic adaptation of parasites to new environments : Plasmodium vivax in Americas(2020), and Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)
Subjects: [SDV.EE]Life Sciences [q-bio]/Ecology, environment, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, adaptive evolution, population genomics, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Plasmodium falciparum, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, host-pathogen interactions, Americas, Molecular Biology, Ecology, Evolution, Behavior and Systematics
Abstract: Plasmodium falciparum, the most virulent agent of human malaria, spread from Africa to all continents following the out-of-Africa human migrations. During the transatlantic slave trade between the 16thand 19thcenturies, it was introduced twice independently to the Americas where it adapted to new environmental conditions (new human populations and mosquito species). Here, we analyzed the genome-wide polymorphisms of 2,635 isolates across the currentP. falciparumdistribution range in Africa, Asia, Oceania, and the Americas to investigate its genetic structure, invasion history, and selective pressures associated with its adaptation to the American environment. We confirmed that American populations originated from Africa with at least two independent introductions that led to two genetically distinct clusters, one in the North (Haiti and Columbia) and one in the South (French Guiana and Brazil), and the admixed Peruvian group. Genome scans revealed recent and more ancient signals of positive selection in the American populations. Particularly, we detected positive selection signals in genes involved in interactions with host (human and mosquito) cells and in genes involved in resistance to malaria drugs in both clusters. We found that some genes were under selection in both clusters. Analyses suggested that for five genes, adaptive introgression between clusters or selection on standing variation was at the origin of this repeated evolution. This study provides new genetic evidence onP. falciparumcolonization history and on its local adaptation in the Americas.
Published: 2023

25. Hepatocellular carcinoma in Peru: A molecular description of an unconventional clinical presentation

Author: J. Contreras-Mancilla, J.P. Cerapio, E. Ruiz, R. Fernández, S. Casavilca-Zambrano, C. Machicado, J.J. Fournié, P. Pineau, S. Bertani, Universidad Peruana Cayetano Heredia (UPCH), Laboratoire Mixte International d'Oncologie Anthropologique Moléculaire = International Joint Laboratory of Molecular Anthropological Oncology (LOAM), Institut de Recherche pour le Développement (IRD [Pérou]), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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 National de la Recherche Scientifique (CNRS), TOUCAN Laboratoire d'Excellence Toulouse Cancer, Instituto Nacional de Enfermedades Neoplasicas [Lima, Pérou] (INEN), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), 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), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Los autores declaran que este trabajo fue apoyado por el ITMO Cáncer de la Alianza Nacional Francesa para las Ciencias de la Vida y la Salud (Aviesan) y del Instituto Nacional francés del Cáncer (INCa) sobre fondos administrados por el Instituto Nacional francés de Salud e Investigación Médica (Inserm) (subvención 21CD025-00), así como por el Programa de Laboratorios Mixtos Internationales (LMI) del Instituto francés de Investigación para el Desarrollo (IRD). JCM reconoce el apoyo financiero del Proyecto Concytec-Banco Mundial «Mejoramiento y Ampliación de los Servicios del Sistema Nacional de Ciencia Tecnología e Innovación Tecnológica» 8682-PE, a través de su unidad ejecutora ProCiencia [08-2018-FONDECYT/BM-Programas de Doctorados en Áreas Estratégicas y Generales]. JPC fue beneficiario de una beca posdoctoral de la Agencia Nacional de Investigación de Francia (ANR) en el marco del Programa de Laboratorios de Excelencia 11-LABX-0068., and ANR-11-LABX-0068,TOUCAN,Analyse intégrée de la résistance dans les cancers hématologiques(2011)
Subjects: DNA methylation, Hepatocellular carcinoma, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Integrative genomics, Peru, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Medicine, Transcriptome
Abstract: International audience; Background. Hepatocellular carcinoma (HCC) is the third most frequent cancer of digestive tract tumors in Peru, with a high mortality rate of 17.7 per 100,000 inhabitants. A significant number of HCC cases in Peru do not follow the classic clinical epidemiology of the disease described in other parts of the world. Those patients present with a distinct transcriptome profile and a singular tumor process, suggesting a particular type of hepatocarcinogenesis in a portion of the Peruvian population. Aim. Our aim was to understand the clinical and biologic involvement of the epigenetic profile (methylation) and gene expression (transcriptome) of HCC in Peruvian patients. Methods. HCC and liver transcriptome and DNA methylation profiles were evaluated in 74 Peruvian patients. Results. When grouped by age, there was greater DNA methylation in younger patients with HCC but no differences with respect to the transcriptomic profile. A high prevalence of the hepatitis B virus (HBV) (> 90%) was also observed in the younger patients with HCC. Enrichment analyses in both molecular profiles pinpointed PRC2 as an important molecular effector of that liver tumor process in Peruvian patients. Conclusion. HCC in Peruvian patients has a unique molecular profile, associated with the presence of HBV, as well as overall DNA hypermethylation related to undifferentiated liver cells or cellular reprogramming.; Introducción. En Perú, el carcinoma hepatocelular (CHC) ocupa el tercer lugar en incidencia entre los tumores del sistema digestivo, y tiene una alta tasa de mortalidad, 17.7 por 100,000 habitantes. La mayoría de los casos reportados no presentan la epidemiología clínica clásica del CHC observado en otras partes del mundo. Además, se ha identificado que estos pacientes presentan un perfil transcriptómico distinto y un proceso tumoral singular, sugiriendo un proceso particular de hepatocarcinogénesis en una fracción de la población peruana. Objetivo. El presente estudio busca comprender la implicancia clínica y biológica del perfil epigenético (metilación) y de expresión de los genes (transcriptómico) del CHC en los pacientes peruanos. Métodos. Se evaluó el perfil de transcriptómico y de metilación de ADN de hígado y CHC en 74 pacientes peruanos. Resultados. El agrupamiento por edades mostró una mayor metilación del ADN en los pacientes jóvenes con CHC, en contraste no se observaron diferencias en el perfil transcriptómico. Adicionalmente, también se evidenció una alta prevalencia del virus de hepatitis B (VHB) (> 90%) en los pacientes jóvenes con CHC. El análisis de enriquecimiento en ambos perfiles moleculares demostró que PRC2 es posiblemente uno de los principales actores moleculares en este proceso tumoral hepático en pacientes peruanos. Conclusión. El CHC peruano presenta un perfil molecular único, asociado a la presencia del VHB, y con una hipermetilación global del ADN asociado a células hepáticas indiferenciadas o a una reprogramación celular.
Published: 2023

26. One model fits all: Combining inference and simulation of gene regulatory networks

Author: Elias Ventre, Ulysse Herbach, Thibault Espinasse, Gérard Benoit, Olivier Gandrillon, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Camille Jordan (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), 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)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Modélisation multi-échelle des dynamiques cellulaires : application à l'hématopoïese (DRACULA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-Inria Lyon, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Biology, genetics and statistics (BIGS), Inria Nancy - Grand Est, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Élie Cartan de Lorraine (IECL), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Probabilités, statistique, physique mathématique (PSPM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANR-18-CE45-0023,SingleStatOmics,Statistique et Apprentissage pour la génomique en cellules uniques(2018), and École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: Ecology, Transcriptional bursting, Lineage commitment, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Gene regulatory networks, Cellular and Molecular Neuroscience, Stochastic gene expression, Computational Theory and Mathematics, Data simulation, Modeling and Simulation, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, [MATH]Mathematics [math], Molecular Biology, Ecology, Evolution, Behavior and Systematics, Single-cell transcriptomics, Time-course profiles, Causal inference
Abstract: The rise of single-cell data highlights the need for a nondeterministic view of gene expression, while offering new opportunities regarding gene regulatory network inference. We recently introduced two strategies that specifically exploit time-course data, where single-cell profiling is performed after a stimulus: HARISSA, a mechanistic network model with a highly efficient simulation procedure, and CARDAMOM, a scalable inference method seen as model calibration. Here, we combine the two approaches and show that the same model driven by transcriptional bursting can be used simultaneously as an inference tool, to reconstruct biologically relevant networks, and as a simulation tool, to generate realistic transcriptional profiles emerging from gene interactions. We verify that CARDAMOM quantitatively reconstructs causal links when the data is simulated from HARISSA, and demonstrate its performance on experimental data collected onin vitrodifferentiating mouse embryonic stem cells. Overall, this integrated strategy largely overcomes the limitations of disconnected inference and simulation.Author summaryGene regulatory network (GRN) inference is an old problem, to which single-cell data has recently offered new challenges and breakthrough potential. Many GRN inference methods based on single-cell transcriptomic data have been developed over the last few years, while GRN simulation tools have also been proposed for generating synthetic datasets with realistic features. However, except for benchmarking purposes, these two fields remain largely disconnected. In this work, building on a combination of two methods we recently described, we show that a particular GRN model can be used simultaneously as an inference tool, to reconstruct a biologically relevant network from time-course single-cell gene expression data, and as a simulation tool, to generate realistic transcriptional profiles in a non-trivial way through gene interactions. This integrated strategy demonstrates the benefits of using the same executable model for both simulation and inference.
Published: 2023

27. Small networks of expressed genes in the whole blood and relationships to profiles in circulating metabolites provide insights in inter-individual variability of feed efficiency in growing pigs

Author: Juigné, Camille, Becker, Emmanuelle, Gondret, Florence, Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Rennes Angers, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Dynamics, Logics and Inference for biological Systems and Sequences (Dyliss), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), and Camille Juigné was supported by a doctoral grant from INRAE (Metaprogramme DigitBio) and Région Bretagne (France).
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.SA.ZOO]Life Sciences [q-bio]/Agricultural sciences/Zootechny, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Transcriptomic dataset was obtained from NCBI’s Gene Expression Omnibus (GEO) Subserie accession number GSE70838 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70838).The metabolomic dataset was retrieved in Jegou et al. [14]. Phenotypic traits and fatty acid composition in plasma are are deposited in the publicly available repository at https://entrepot.recherche.data.gouv.fr/dataset.xhtml?persistentId=doi:10.57745/TM2ANC.The adjacency matrix is available at https://data-access.cesgo.org/index.php/s/YPz0J2ItxIEuN5M.We provide R notebooks detailing the analysis https://github.com/cjuigne/multiomics_and_feed_efficiency; Background: Feed efficiency is a research priority to support a sustainable meat production. It is recognized as a complex trait that integrates multiple biological pathways orchestrated in and by various tissues. This study aims to determine networks between biological entities to explain inter-individual variation of feed efficiency in growing pigs. Results: The feed conversion ratio (FCR), a measure of feed efficiency, and its two component traits, average daily gain and average daily feed intake, were obtained from 47 growing pigs from a divergent selection for residual feed intake and fed high-starch or high-fat high-fiber diets during 58 days. Datasets of transcriptomics (60 k porcine microarray) in the whole blood and metabolomics (1H-NMR analysis and target gas chromatography) in plasma were available for all pigs at the end of the trial. A weighted gene co-expression network was built from the transcriptomics dataset, resulting in 33 modules of coexpressed molecular probes. The eigengenes of eight of these modules were significantly (P ≤ 0.05) or tended to be (0.05 < P ≤ 0.10) correlated to FCR. Great homogeneity in the enriched biological pathways was observed in these modules, suggesting co-expressed and co-regulated constitutive genes. They were mainly enriched in genes participating to immune and defense-related processes. They were also generally associated with growth rate and percentage of lean mass. In the network, only one module composed of genes participating to the response to substances, was significantly associated with daily feed intake and body adiposity. The profiles in circulating metabolites and fatty acids of plasma were summarized by weighted linear combinations using a dimensionality reduction method. Close association was notably found between a module composed of co-expressed genes participating to T cell receptor signaling and cell development process in the whole blood and related to FCR, and the circulating concentrations of omega-3 fatty acids in plasma. Conclusion: These systemic approaches have highlighted networks of entities driving key biological processes involved in the phenotypic difference in feed efficiency between animals. Connecting transcriptomics and metabolic levels together had some additional benefits.
Published: 2023

28. Evolutionary history of the transposon-invaded Pithoviridae genomes

Author: Sofia Rigou, Alain Schmitt, Jean-Marie Alempic, Audrey Lartigue, Peter Vendloczki, Chantal Abergel, Jean-Michel Claverie, Matthieu Legendre, Information génomique et structurale (IGS), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and ANR-22-CE12-0041,PandoNovo,Création de gènes de novo chez les Pandoravirus géants(2022)
Subjects: [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology
Abstract: Pithoviruses are amoeba-infecting giant viruses possessing the largest viral particles known so far. Since the discovery ofPithovirus sibericum, recovered from a 30,000-y-old permafrost sample, other pithoviruses, and related cedratviruses, were isolated from various terrestrial and aquatic samples. Here we report the isolation and genome sequencing of two strains ofPithoviridaefrom soil samples, in addition to three other recent isolates. Using the 12 available genome sequences, we conducted a thorough comparative genomics study of thePithoviridaefamily to decipher the organization and evolution of their genomes. Our study reveals a non-uniform genome organization in two main regions: one concentrating core genes, and another gene duplications. We also found thatPithoviridaegenomes are more conservative than other families of giant viruses, with a low and stable proportion (5% to 7%) of genes originating from horizontal transfers. Genome size variation within the family is mainly due to variations in gene duplication rates (from 14% to 28%) and massive invasion by miniature inverted-repeats transposable elements (MITEs). While these repeated elements are absent from cedratviruses, repeat-rich regions cover as much as a quarter of the pithoviruses genomes. These regions, identified using a dedicated pipeline, are hotspots of mutations, gene capture events and genomic rearrangements, that likely contribute to their evolution.
Published: 2023

29. Telomeres, the loop tying cancer to organismal life‐histories

Author: Beata Ujvari, Nynke Raven, Thomas Madsen, Marcel Klaassen, Antoine M. Dujon, Aaron G. Schultz, Leonard Nunney, Jean‐François Lemaître, Mathieu Giraudeau, Frédéric Thomas, Deakin University [Burwood], University of California [Riverside] (UC Riverside), University of California (UC), Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), LIttoral ENvironnement et Sociétés (LIENSs), La Rochelle Université (ULR)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches Ecologiques et Evolutives sur le Cancer (MIVEGEC-CREEC), Processus Écologiques et Évolutifs au sein des Communautés (PEEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Deakin LES Entrepreneurship Funds (2020-2021), MAVA Foundation, ARC Linkage, Grant/Award Number: LP170101105, Deakin SEBE, Centre National de la Recherche Scientifique, ANR TRANSCAN, Grant/Award Number: ANR- 18- CE35- 0009, HolsworthWildlifeResearchEndowment, and ANR-18-CE35-0009,TRANSCAN,ECOLOGIE ET EVOLUTION DES CANCERS TRANSMISSIBLES(2018)
Subjects: [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, Mate-choice, MESH: Humans, MESH: Biological Evolution, [SDV.CAN]Life Sciences [q-bio]/Cancer, Predator-prey interactions, Pollution, Peto's paradox, Parental effect, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Telomere Shortening, Genetics, Parasites, MESH: Ecosystem, MESH: Neoplasms, MESH: Telomere, Cell proliferation, Ecology, Evolution, Behavior and Systematics
Abstract: International audience; Recent developments in telomere and cancer evolutionary ecology demonstrate a very complex relationship between the need of tissue repair and controlling the emergence of abnormally proliferating cells. The trade-off is balanced by natural and sexual selection and mediated via both intrinsic and environmental factors. Here, we explore the effects of telomere-cancer dynamics on life history traits and strategies as well as on the cumulative effects of genetic and environmental factors. We show that telomere-cancer dynamics constitute an incredibly complex and multifaceted process. From research to date, it appears that the relationship between telomere length and cancer risk is likely nonlinear with good evidence that both (too) long and (too) short telomeres can be associated with increased cancer risk. The ability and propensity of organisms to respond to the interplay of telomere dynamics and oncogenic processes, depends on the combination of its tissue environments, life history strategies, environmental challenges (i.e., extreme climatic conditions), pressure by predators and pollution, as well as its evolutionary history. Consequently, precise interpretation of telomere-cancer dynamics requires integrative and multidisciplinary approaches. Finally, incorporating information on telomere dynamics and the expression of tumour suppressor genes and oncogenes could potentially provide the synergistic overview that could lay the foundations to study telomere-cancer dynamics at ecosystem levels.
Published: 2022

30. The ‘Alu-ome’ shapes the epigenetic environment of regulatory elements controlling cellular defense

Author: Mickael Costallat, Eric Batsché, Christophe Rachez, Christian Muchardt, Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and MUCHARDT, Christian
Subjects: Epigenomics, biology, Alu element, RNA polymerase II, Promoter, Regulatory Sequences, Nucleic Acid, Cell biology, Epigenesis, Genetic, Histone Code, Transcription (biology), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], DNA methylation, biology.protein, Genetics, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], H3K4me3, Epigenetics, Enhancer, Promoter Regions, Genetic
Abstract: Promoters and enhancers are sites of transcription initiation (TSSs) and carry active histone modifications, including H3K4me1, H3K4me3, and H3K27ac. Yet, the principles governing the boundaries of such regulatory elements are still poorly characterized. Alu elements are good candidates for a boundary function, being highly abundant in gene-rich regions, while essentially excluded from regulatory elements. Here, we show that the interval from the TSS to the first upstream Alu accommodates essentially all H3K4me3 marks, while excluding DNA methylation. In contrast, enhancer-enriched H3K4me1 and H3K27ac marks eventually cross the first-Alu limit, consistent with enhancer-annotation occasionally overlapping with Alu elements. Remarkably, the average length of TSS-to-first Alu intervals greatly varies in-between tissues, being longer in stem- and shorter in immune-cells. Shortest TSS-to-Alu intervals were observed at promoters active in T cells, particularly at immune genes, correlating with serendipitous RNA polymerase II transcription and accumulation of H3K4me1 signal at the first-Alu. At several T-cell first-Alus, the DNA methylation was further found to evolved with age, regressing from young to middle-aged, then recovering later in life. Thus, the first-Alu upstream of TSSs functions as a dynamic boundary for regulatory elements, initiating the upstream DNA-methylation landscape, while also participating in the recording of immune gene transcriptional events.
Published: 2022

31. Single-cell differentiation trajectories define early stages of a human cutaneous T-cell lymphoma

Author: Juan‐Pablo Cerapio, Marion Perrier, Fréderic Pont, Camille Laurent, Stéphane Bertani, Jean‐Jacques Fournie, Centre de Recherches en Cancérologie de Toulouse (CRCT), 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 National de la Recherche Scientifique (CNRS), Laboratoire Mixte International d'Oncologie Anthropologique Moléculaire = International Joint Laboratory of Molecular Anthropological Oncology (LOAM), Institut de Recherche pour le Développement (IRD [Pérou]), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), 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), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)
Subjects: Lymphoma, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], hemic and lymphatic diseases, Pseudotime, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, scRNAseq, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Gamma delta T cells, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract: International audience; Aim: The aim of this article is to characterize in detail the γδ T lymphocytes from an adult patient with primary cutaneous T-cell lymphoma of γδ subtype (γδ CTCL). Methods: Here this article reports trajectory mapping on high-resolution differentiation trajectories of γδ T lymphocytes digitally extracted from a scRNAseq dataset. Results: In the patch-to-plaque progression of CTCL, the TCRVγnon9 subset of γδ T cells differentiated from naive T cells (Tn) and central memory T cells (Tcm) to abundant effector memory T cells (Tem) while other cutaneous γδ T and CD8 T cells remained unchanged. Conclusions: This transcriptomic switch underlies the emergence of a CTCL-like progression of the TCRVγnon9 γδ T subtype and suggests new routes for treating these diseases.
Published: 2022

32. Will the genomics revolution finally solve the Salmo systematics?

Author: Christelle Tougard, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: animal diseases, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], nuclear DNA, Salmo trutta, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, mitochondrial DNA, [SDV.BID]Life Sciences [q-bio]/Biodiversity, Aquatic Science, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, next-generation sequencing technologies, molecular phylogeny
Abstract: International audience; On one hand, studies on Salmo biological variations during the last centuries have led to the morphological description of several Salmo species (>50). On the other hand, Salmo trutta is seen as a polymorphic species, i.e. including populations with different morphotypes and ecotypes, subdivided into nine genetically divergent evolutionary lineages. For 30 years, phylogeographic and phylogenetic investigations tried to solve the Salmo systematic problem using the mitochondrial control region, sometimes combined with other mitochondrial (e.g. protein coding region or rRNA genes) or nuclear (e.g. allozymes or microsatellites) markers. With the advent of high throughput next-generation sequencing, complete mitogenomes were made available for Salmo phylogenetic studies. Even better, complete genome or chromosomes with annotations as well as genes of interest can now be loaded from public database. However, in the genomic era, some challenges still need to be addressed such as an appropriate taxon sampling or the identification of orthologous genes before having an accurate phylogeny. In the present review, I examine how traditional molecular markers contributed to our knowledge of trout systematics, and what we can expect from the genomics revolution.
Published: 2022

33. CYCLHAD: A French Facility Dedicated for Research and Treatment in Hadrontherapy

Author: Chevalier, François, Lesueur, P., Gaubert, G., Accueil et Recherche en Radiobiologie des Ions Accélérés (ARIA), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de radiothérapie Guillaume le Conquérant (CGLC), Imagerie et Stratégies Thérapeutiques pour les Cancers et Tissus cérébraux (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), and Pantechnik
Subjects: Nuclear and High Energy Physics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology
Abstract: International audience
Published: 2022

34. L1 chimeric transcripts are expressed in healthy brain and their deregulation in glioma follows that of their host locus

Author: Marie-Elisa Pinson, Franck Court, Aymeric Masson, Yoan Renaud, Allison Fantini, Ophélie Bacoeur-Ouzillou, Marie Barriere, Bruno Pereira, Pierre-Olivier Guichet, Emmanuel Chautard, Lucie Karayan-Tapon, Pierre Verrelle, Philippe Arnaud, Catherine Vaurs-Barrière, BARRIERE, Catherine, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de Cancérologie Biologique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut Curie [Paris], Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS)
Subjects: Retroelements, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, [SDV.CAN]Life Sciences [q-bio]/Cancer, Glioma, General Medicine, Long Interspersed Nucleotide Elements, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Humans, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Promoter Regions, Genetic, Molecular Biology, Genetics (clinical)
Abstract: Besides the consequences of retrotransposition, long interspersed element 1 (L1) retrotransposons can affect the host genome through their antisense promoter. In addition to the sense promoter, the evolutionarily recent L1 retrotransposons, which are present in several thousand copies, also possess an anti-sense promoter that can produce L1 chimeric transcripts (LCT) composed of the L1 5′ UTR followed by the adjacent genomic sequence. The full extent to which LCT expression occurs in a given tissue and whether disruption of the defense mechanisms that normally control L1 retrotransposons affects their expression and function in cancer cells, remain to be established. By using CLIFinder, a dedicated bioinformatics tool, we found that LCT expression was widespread in normal brain and aggressive glioma samples, and that approximately 17% of recent L1 retrotransposons, from the L1PA1 to L1PA7 subfamilies, were involved in their production. Importantly, the transcriptional activities of the L1 antisense promoters and of their host loci were coupled. Accordingly, we detected LCT-producing L1 retrotransposons mainly in transcriptionally active genes and genomic loci. Moreover, changes in the host genomic locus expression level in glioma were associated with a similar change in LCT expression level, regardless of the L1 promoter methylation status. Our findings support a model in which the host genomic locus transcriptional activity is the main driving force of LCT expression. We hypothesize that this model is more applicable when host gene and LCT are transcribed from the same strand.
Published: 2022

35. Optimal transport improves cell–cell similarity inference in single-cell omics data

Author: Laura Cantini, Huizing G, Gabriel Peyré, Institut de biologie de l'Ecole Normale Supérieure (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Ecole Normale Supérieure, Université Marien Ngouabi, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-20-CE45-0015,scMOmix,Méthodes pour l'intégration de données multi-omiques en cellule-unique(2020), Cantini, Laura, Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Analyse (DMA), Département de Mathématiques et Applications - ENS Paris (DMA), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Méthodes pour l'intégration de données multi-omiques en cellule-unique - - scMOmix2020 - ANR-20-CE45-0015 - AAPG2020 - VALID, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), and PaRis Artificial Intelligence Research InstitutE - - PRAIRIE2019 - ANR-19-P3IA-0001 - P3IA - VALID
Subjects: Statistics and Probability, [SDV]Life Sciences [q-bio], Inference, [MATH] Mathematics [math], Biochemistry, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Similarity (network science), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [MATH]Mathematics [math], Molecular Biology, 030304 developmental biology, Profiling (computer programming), 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], business.industry, Pattern recognition, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Pearson product-moment correlation coefficient, 3. Good health, [STAT] Statistics [stat], Computer Science Applications, [SDV] Life Sciences [q-bio], [STAT]Statistics [stat], Identification (information), Computational Mathematics, Computational Theory and Mathematics, Metric (mathematics), Benchmark (computing), symbols, Probability distribution, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Artificial intelligence, business, 030217 neurology & neurosurgery
Abstract: Motivation High-throughput single-cell molecular profiling is revolutionizing biology and medicine by unveiling the diversity of cell types and states contributing to development and disease. The identification and characterization of cellular heterogeneity are typically achieved through unsupervised clustering, which crucially relies on a similarity metric. Results We here propose the use of Optimal Transport (OT) as a cell–cell similarity metric for single-cell omics data. OT defines distances to compare high-dimensional data represented as probability distributions. To speed up computations and cope with the high dimensionality of single-cell data, we consider the entropic regularization of the classical OT distance. We then extensively benchmark OT against state-of-the-art metrics over 13 independent datasets, including simulated, scRNA-seq, scATAC-seq and single-cell DNA methylation data. First, we test the ability of the metrics to detect the similarity between cells belonging to the same groups (e.g. cell types, cell lines of origin). Then, we apply unsupervised clustering and test the quality of the resulting clusters. OT is found to improve cell–cell similarity inference and cell clustering in all simulated and real scRNA-seq data, as well as in scATAC-seq and single-cell DNA methylation data. Availability and implementation All our analyses are reproducible through the OT-scOmics Jupyter notebook available at https://github.com/ComputationalSystemsBiology/OT-scOmics. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2022

36. RCDPeaks: memory-efficient density peaks clustering of long molecular dynamics

Author: Daniel Platero-Rochart, Roy González-Alemán, Erix W Hernández-Rodríguez, Fabrice Leclerc, Julio Caballero, Luis Montero-Cabrera, Laboratory of Computational and Theoretical Chemistry, Faculty of Chemistry, University of Havana, Havana, Cuba (LQCT), Universidad de La Habana [Cuba], Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Universidad Catolica Del Maule, Departamento de Bioinformática, Facultad de Ingeniería, Centro de Bioinformática, Simulación y Modelado (CBSM), Universidad de Talca, Talca, Chile, and Universidad de Talca
Subjects: [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Statistics and Probability, Computational Mathematics, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Computational Theory and Mathematics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Molecular Biology, Biochemistry, [CHIM.CHEM]Chemical Sciences/Cheminformatics, Computer Science Applications
Abstract: Motivation Density Peaks is a widely spread clustering algorithm that has been previously applied to Molecular Dynamics (MD) simulations. Its conception of cluster centers as elements displaying both a high density of neighbors and a large distance to other elements of high density, particularly fits the nature of a geometrical converged MD simulation. Despite its theoretical convenience, implementations of Density Peaks carry a quadratic memory complexity that only permits the analysis of relatively short trajectories. Results Here, we describe DP+, an exact novel implementation of Density Peaks that drastically reduces the RAM consumption in comparison to the scarcely available alternatives designed for MD. Based on DP+, we developed RCDPeaks, a refined variant of the original Density Peaks algorithm. Through the use of DP+, RCDPeaks was able to cluster a one-million frames trajectory using less than 4.5 GB of RAM, a task that would have taken more than 2 TB and about 3× more time with the fastest and less memory-hunger alternative currently available. Other key features of RCDPeaks include the automatic selection of parameters, the screening of center candidates and the geometrical refining of returned clusters. Availability and implementation The source code and documentation of RCDPeaks are free and publicly available on GitHub (https://github.com/LQCT/RCDPeaks.git). Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2022

37. TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV

Author: Matkovic, R., Morel, M., Lanciano, S., Larrous, P., Martin, B., Bejjani, F., Vauthier, V., Hansen, M.M.K., Emiliani, S., Cristofari, G., Gallois-Montbrun, S., Margottin-Goguet, F., Emiliani, Stephane, 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), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Radboud University [Nijmegen]
Subjects: RNA Stability, Science, Gene Expression, HIV Infections, Epigenetic Repression, Article, Histones, Proviruses, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Schizosaccharomyces, Humans, HIV Long Terminal Repeat, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Retrovirus, Nuclear Proteins, Gene silencing, Histone-Lysine N-Methyltransferase, Chromatin Assembly and Disassembly, Phosphoproteins, HIV-2, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA Polymerase II, Restriction factors, Biophysical Chemistry, HeLa Cells, Transcription Factors
Abstract: The Human Silencing Hub (HUSH) complex constituted of TASOR, MPP8 and Periphilin recruits the histone methyl-transferase SETDB1 to spread H3K9me3 repressive marks across genes and transgenes in an integration site-dependent manner. The deposition of these repressive marks leads to heterochromatin formation and inhibits gene expression, but the underlying mechanism is not fully understood. Here, we show that TASOR silencing or HIV-2 Vpx expression, which induces TASOR degradation, increases the accumulation of transcripts derived from the HIV-1 LTR promoter at a post-transcriptional level. Furthermore, using a yeast 2-hybrid screen, we identify new TASOR partners involved in RNA metabolism including the RNA deadenylase CCR4-NOT complex scaffold CNOT1. TASOR and CNOT1 synergistically repress HIV expression from its LTR. Similar to the RNA-induced transcriptional silencing complex found in fission yeast, we show that TASOR interacts with the RNA exosome and RNA Polymerase II, predominantly under its elongating state. Finally, we show that TASOR facilitates the association of RNA degradation proteins with RNA polymerase II and is detected at transcriptional centers. Altogether, we propose that HUSH operates at the transcriptional and post-transcriptional levels to repress HIV proviral expression., The human silencing hub (HUSH) complex, which includes TASOR, deposits repressive marks on HIV proviruses, resulting in gene repression. Here, Matkovic et al. show that TASOR interacts with RNA Polymerase II, predominantly under its elongating state, and RNA degradation proteins to repress HIV provirus expression.
Published: 2022

38. RIP140 regulates POLK gene expression and the response to alkylating drugs in colon cancer cells

Author: Pascale Palassin, Marion Lapierre, Sandrine Bonnet, Marie-Jeanne Pillaire, Balázs Győrffy, Catherine Teyssier, Stéphan Jalaguier, Jean-Sébastien Hoffmann, Vincent Cavaillès, Audrey Castet-Nicolas, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), Semmelweis University [Budapest], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), 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 Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Herrada, Anthony
Subjects: Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Pol Kappa, Colorectal cancer, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, RIP140, [SDV.CAN] Life Sciences [q-bio]/Cancer, translesion DNA synthesis polymerase, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pharmacology (medical), genome stability
Abstract: International audience; Aim: The transcription factor RIP140 (receptor interacting protein of 140 kDa) is involved in intestinal tumorigenesis. It plays a role in the control of microsatellite instability (MSI), through the regulation of MSH2 and MSH6 gene expression. The aim of this study was to explore its effect on the expression of POLK, the gene encoding the specialized translesion synthesis (TLS) DNA polymerase κ known to perform accurate DNA synthesis at microsatellites.Methods: Different mouse models and engineered human colorectal cancer (CRC) cell lines were used to analyze by RT-qPCR, while Western blotting and luciferase assays were used to elucidate the role of RIP140 on POLK gene expression. Published DNA microarray datasets were reanalyzed. The in vitro sensitivity of CRC cells to methyl methane sulfonate and cisplatin was determined.Results: RIP140 positively regulates, at the transcriptional level, the expression of the POLK gene, and this effect involves, at least partly, the p53 tumor suppressor. In different cohorts of CRC biopsies (with or without MSI), a strong positive correlation was observed between RIP140 and POLK gene expression. In connection with its effect on POLK levels and the TLS function of this polymerase, the cellular response to methyl methane sulfonate was increased in cells lacking the Rip140 gene. Finally, the association of RIP140 expression with better overall survival of CRC patients was observed only when the corresponding tumors exhibited low levels of POLK, thus strengthening the functional link between the two genes in human CRC.Conclusion: The regulation of POLK gene expression by RIP140 could thus contribute to the maintenance of microsatellite stability, and more generally to the control of genome integrity.
Published: 2022

39. Does size matter? A proteomics-informed comparison of the effects of polystyrene beads of different sizes on macrophages

Author: Véronique Collin-Faure, Bastien Dalzon, Julie Devcic, Hélène Diemer, Sarah Cianférani, Thierry Rabilloud, Protéomique pour la Microbiologie, l'Immunologie et la Toxicologie (PROMIT), Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Infrastructure Nationale de Protéomique, FR2048 ProFI, and ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017)
Subjects: [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Materials Science (miscellaneous), [SDV.IMM]Life Sciences [q-bio]/Immunology, General Environmental Science
Abstract: International audience; Plastics are one of the most preoccupying emerging pollutants. Macroplastics released into the environment degrade into microplastics and nanoplastics. Because of their small size, these micro and nano plastic particles can enter the food chain and, in addition to their ecotoxicological effects, contaminate humans with still unknown biological effects. Plastics being particulate pollutants, they are handled in the human body by scavenger cells such as macrophages, which are important players in the immune system. In order to get a better appraisal of the effects of plastic particles on macrophages, we have studied the effects of unmodified polystyrene particles of 0.1, 1 and 10 micrometers of diameter, by a combination of proteomics and targeted validation experiments. Proteomics showed important adaptive changes of the proteome in response to exposure to plastics, with more than one third of the detected proteins showing a significance change in their abundance in response to cell exposure to at least one plastic bead size. These changes affected for example mitochondrial, lysosomal or cytoskeletal proteins. Although an increase in the mitochondrial transmembrane potential was detected in response to 10 micrometer beads, no alteration in cell viability was observed. Similarly, no lysosomal dysfunction and no alteration in the phagocytic capability of the cells was observed in response to exposure to plastics. When the inflammatory response was examined, no increase in the secretion of tumor necrosis factor or interleukin 6 was observed. Oppositely, the secretion of these cytokines in response to lipopolysaccharide was observed after exposure to plastics, which suggested a decreased ability of macrophages to respond to bacterial infection. In conclusion, these results provide a better understanding of the responses of macrophages to exposure to polystyrene particles of different sizes.
Published: 2022

40. Comprehensive transcriptome-wide analysis of spliceopathy correction of myotonic dystrophy using CRISPR-Cas9 in iPSCs-derived cardiomyocytes

Author: Kshitiz Singh, Denis Furling, Sumitava Dastidar, Marinee Chuah, Thierry VandenDriessche, Debanjana Majumdar, Jaitip Tipanee, Arnaud F. Klein, Vrije Universiteit Brussel (VUB), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Basic (bio-) Medical Sciences, Division of Gene Therapy & Regenerative Medicine, Faculty of Medicine and Pharmacy, Centre de recherche en Myologie – U974 SU-INSERM, and Furling, Denis
Subjects: Candidate gene, TNNT2, Research & Experimental Medicine, Transcriptome, chemistry.chemical_compound, 0302 clinical medicine, FUNCTIONAL-CHARACTERIZATION, cardiomyogenic differentiation, Drug Discovery, Myotonic Dystrophy, MBNL1, ribonuclear foci, Myocytes, Cardiac, Gene Editing, Genetics & Heredity, 0303 health sciences, CHLORIDE CHANNEL, RNA-Binding Proteins, MUSCLE, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cell biology, DIFFERENTIATION, Medicine, Research & Experimental, RNA splicing, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Molecular Medicine, MESSENGER-RNA, Life Sciences & Biomedicine, EXPRESSION, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, PROTEINS, CRISPR ribonucleoprotein, Induced Pluripotent Stem Cells, Biology, spliceopathy, Myotonic dystrophy, Myotonin-Protein Kinase, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, CACNA1H, Humans, Molecular Biology, 030304 developmental biology, Pharmacology, Science & Technology, Biochemistry, Genetics and Molecular Biology(all), Alternative splicing, alternate splicing, medicine.disease, GENE, Alternative Splicing, Biotechnology & Applied Microbiology, chemistry, biology.protein, SOMATIC-CELLS, Calmodulin-Binding Proteins, CRISPR-Cas Systems, EMBRYONIC STEM-CELLS, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery
Abstract: CTGrepeat expansion (CTGexp) is associated with aberrant alternate splicing that contributes to cardiac dysfunction in myotonic dystrophy type 1 (DM1). Excision of thisCTGexprepeat using CRISPR-Cas resulted in the disappearance of punctate ribonuclear foci in cardiomyocyte-like cells derived from DM1-induced pluripotent stem cells (iPSCs). This was associated with correction of the underlying spliceopathy as determined byRNA sequencingand alternate splicing analysis. Certain genes were of particular interest due to their role in cardiac development, maturation, and function (TPM4,CYP2J2,DMD,MBNL3,CACNA1H,ROCK2,ACTB) or their association with splicing (SMN2,GCFC2,MBNL3). Moreover, while comparing isogenic CRISPR-Cas9-corrected versus non-corrected DM1 cardiomyocytes, a prominent difference in the splicing pattern for a number of candidate genes was apparent pertaining to genes that are associated with cardiac function (TNNT,TNNT2,TTN,TPM1,SYNE1,CACNA1A,MTMR1,NEBL,TPM1),cellular signaling(NCOR2,CLIP1,LRRFIP2,CLASP1,CAMK2G), and other DM1-related genes (i.e.,NUMA1,MBNL2,LDB3) in addition to the disease-causingDMPKgene itself. Subsequent validation using a selected gene subset, includingMBNL1,MBNL2,INSR,ADD3, andCRTC2, further confirmed correction of the spliceopathy followingCTGexprepeat excision. To our knowledge, the present study provides the first comprehensive unbiased transcriptome-wide analysis of the differential splicing landscape in DM1 patient-derived cardiac cells after excision of theCTGexprepeat using CRISPR-Cas9, showing reversal of the abnormal cardiac spliceopathy in DM1.
Published: 2022

41. Identifying the Best Approximating Model in Bayesian Phylogenetics: Bayes Factors, Cross-Validation or wAIC?

Author: Nicolas Lartillot, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon
Subjects: [STAT.AP]Statistics [stat]/Applications [stat.AP], [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Ecology, Evolution, Behavior and Systematics
Abstract: There is still no consensus as to how to select models in Bayesian phylogenetics, and more generally in applied Bayesian statistics. Bayes factors are often presented as the method of choice, yet other approaches have been proposed, such as cross-validation or information criteria. Each of these paradigms raises specific computational challenges, but they also differ in their statistical meaning, being motivated by different objectives: either testing hypotheses or finding the best-approximating model. These alternative goals entail different compromises, and as a result, Bayes factors, cross-validation, and information criteria may be valid for addressing different questions. Here, the question of Bayesian model selection is revisited, with a focus on the problem of finding the best-approximating model. Several model selection approaches were re-implemented, numerically assessed and compared: Bayes factors, cross-validation (CV), in its different forms (k-fold or leave-one-out), and the widely applicable information criterion (wAIC), which is asymptotically equivalent to leave-one-out cross-validation (LOO-CV). Using a combination of analytical results and empirical and simulation analyses, it is shown that Bayes factors are unduly conservative. In contrast, CV represents a more adequate formalism for selecting the model returning the best approximation of the data-generating process and the most accurate estimates of the parameters of interest. Among alternative CV schemes, LOO-CV and its asymptotic equivalent represented by the wAIC, stand out as the best choices, conceptually and computationally, given that both can be simultaneously computed based on standard Markov chain Monte Carlo runs under the posterior distribution. [Bayes factor; cross-validation; marginal likelihood; model comparison; wAIC.]
Published: 2023

42. Identification and characterization of thousands of bacteriophage satellites across bacteria

Author: Jorge A Moura de Sousa, Alfred Fillol-Salom, José R Penadés, Eduardo P C Rocha, Génomique évolutive des Microbes / Microbial Evolutionary Genomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Imperial College London, We acknowledge funding from Equipe FRM (Fondation pour la Recherche Médicale): EQU201903007835, Laboratoire d’Excellence IBEID Integrative Biology of Emerging Infectious Diseases [ANR LBX-62 IBEID AAP BOURSE S2I ROCHA]. This work used the computational and storage services (TARS cluster) provided by the IT department at Institut Pasteur, Paris., We thank Kim Seed for comments and suggestions on earlier versions of the manuscript, Graham Hatfull for helpful discussion regarding the PhiRv1 and PhiRv2 elements in M. tuberculosis, and Bertrand Néron and Fabien Mareuil from the Institut Pasteur’s Bioinformatics and Biostatistics Hub for help in the development of the Docker and Galaxy version of SatelliteFinder., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: Horizontal Gene Transfer, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Mobile Genetic Elements, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Comparative Genomics, Phage Satellites, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: Bacteriophage-bacteria interactions are affected by phage satellites, elements that exploit phages for transfer between bacterial cells. Satellites can encode defense systems, antibiotic resistance genes, and virulence factors, but their number and diversity are unknown for lack of a tool to identify them. We developed a flexible and updateable program to identify satellites in bacterial genomes – SatelliteFinder – and use it to identify the best described families: P4-like, phage inducible chromosomal islands (PICI), capsid-forming PICI, and phage-inducible chromosomal island-like elements (PLE). We vastly expanded the number of described elements to ∼5000, finding hundreds of bacterial genomes with two different families of satellites, and dozens of Escherichia coli genomes with three. Most satellites were found in Proteobacteria and Firmicutes, but some are in novel taxa such as Actinobacteria. We characterized the gene repertoires of satellites, which are variable in size and composition, and their genomic organization, which is very conserved. With the partial exception of PICI and cfPICI, there are few homologous core genes between families of satellites, and even fewer homologous to phages. Hence, phage satellites are ancient, diverse, and probably evolved multiple times independently. Occasionally, core genes of a given family of satellites are found in another, suggesting gene flow between different satellites. Given the many elements found in spite of our conservative approach, the many bacteria infected by phages that still lack known satellites, and the recent proposals for novel families, we speculate that we are at the beginning of the discovery of massive numbers and types of satellites. SatelliteFinder is accessible for the community as a Galaxy service at https://galaxy.pasteur.fr/root?tool_id=toolshed.pasteur.fr/repos/fmareuil/satellitefinder/SatelliteFinder/0.9
Published: 2023

43. Ribosomal RNA (rRNA) sequences from 33 globally distributed mosquito species for improved metagenomics and species identification

Author: Cassandra Koh, Lionel Frangeul, Hervé Blanc, Carine Ngoagouni, Sébastien Boyer, Philippe Dussart, Nina Grau, Romain Girod, Jean-Bernard Duchemin, Maria-Carla Saleh, Virus et Interférence ARN - Viruses and RNA Interference, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur de Bangui, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur du Cambodge, Unité de Virologie / Virology Unit [Phnom Penh], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Pasteur de Madagascar, Vectopôle Amazonien Emile Abonnenc [Cayenne, Guyane française], Institut Pasteur de la Guyane, and This work was supported by the Defence Advanced Research Projects Agency PREEMPT program managed by Dr. Rohit Chitale and Dr. Kerri Dugan [Cooperative Agreement HR001118S0017]
Subjects: General Immunology and Microbiology, [SDV]Life Sciences [q-bio], [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], General Neuroscience, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract: Total RNA sequencing (RNA-seq) is an important tool in the study of mosquitoes and the RNA viruses they vector as it allows assessment of both host and viral RNA in specimens. However, there are two main constraints. First, as with many other species, abundant mosquito ribosomal RNA (rRNA) serves as the predominant template from which sequences are generated, meaning that the desired host and viral templates are sequenced far less. Second, mosquito specimens captured in the field must be correctly identified, in some cases to the sub-species level. Here, we generate mosquito rRNA datasets which will substantially mitigate both of these problems. We describe a strategy to assemble novel rRNA sequences from mosquito specimens and produce an unprecedented dataset of 234 full-length 28S and 18S rRNA sequences of 33 medically important species from countries with known histories of mosquito-borne virus circulation (Cambodia, the Central African Republic, Madagascar, and French Guiana). These sequences will allow both physical and computational removal of rRNA from specimens during RNA-seq protocols. We also assess the utility of rRNA sequences for molecular taxonomy and compare phylogenies constructed using rRNA sequences versus those created using the gold standard for molecular species identification of specimens—the mitochondrial cytochrome c oxidase I (COI) gene. We find that rRNA- and COI-derived phylogenetic trees are incongruent and that 28S and concatenated 28S+18S rRNA phylogenies reflect evolutionary relationships that are more aligned with contemporary mosquito systematics. This significant expansion to the current rRNA reference library for mosquitoes will improve mosquito RNA-seq metagenomics by permitting the optimization of species-specific rRNA depletion protocols for a broader range of species and streamlining species identification by rRNA sequence and phylogenetics.
Published: 2023

44. Combined in vivo and in situ genome-resolved metagenomics reveals novel symbiotic nitrogen fixing interactions between non-cyanobacterial diazotrophs and microalgae

Author: UDITA CHANDOLA, CAMILLE TROTTIER, MARINNA GAUDIN, ERIC MANIRAKIZA, SAMUEL MENICOT, ISABELLE LOUVET, THOMAS LACOUR, TIMOTHEE CHAUMIER, ATSUKO TANAKA, Samuel Chaffron, Leila Tirichine, Unité en Sciences Biologiques et Biotechnologies de Nantes (US2B), Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Laboratoire des Sciences du Numérique de Nantes (LS2N), Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École Centrale de Nantes (Nantes Univ - ECN), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ), Global Oceans Systems Ecology & Evolution - Tara Oceans (GOSEE), Université de Perpignan Via Domitia (UPVD)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Aix Marseille Université (AMU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Université de Toulon (UTLN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche pour le Développement (IRD [France-Nord])-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-European Molecular Biology Laboratory (EMBL)-École Centrale de Nantes (Nantes Univ - ECN), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université australe du Chili, Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Laboratoire Physiologie des Microalgues (PHYSALG), Physiologie et Toxines des Microalgues Toxiques et Nuisibles (PHYTOX), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Department of Chemistry, Biology and Marine Science, University of the Ryukyus [Okinawa], Unité en Sciences Biologiques et Biotechnologies de Nantes - UMR CNRS 6286 (US2B), Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche Génomique Info (URGI), Institut National de la Recherche Agronomique (INRA), National Cardiovascular Center, Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Tara Oceans-GOSEE (FR2022), and Faculty of Science - University of Nantes
Subjects: [SDV.EE.ECO]Life Sciences [q-bio]/Ecology, environment/Ecosystems, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDE.BE]Environmental Sciences/Biodiversity and Ecology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.EE.IEO]Life Sciences [q-bio]/Ecology, environment/Symbiosis
Abstract: Non-cyanobacteria diazotrophs (NCDs) were shown to dominate in surface waters shifting the long-held paradigm of cyanobacteria dominance and raising fundamental questions on how these putative heterotrophic bacteria thrive in sunlit oceans. Here, we report an unprecedented finding in the widely used model diatom Phaeodactylum tricornutum (Pt) of NCDs sustaining diatom cells in the absence of bioavailable nitrogen. We identified PtNCDs using metagenomics sequencing and detected nitrogenase gene in silico and/or by PCR. We demonstrated nitrogen fixation in PtNCDs and their close genetic affiliation with NCDs from the environment. We showed the wide occurrence of this type of symbiosis with the isolation of NCDs from other microalgae, their identification in the environment, and predicted their associations with photosynthetic microalgae. Overall, this study provides evidence for a previously overlooked symbiosis using a multidisciplinary model-based approach, which will help understand the different players driving global marine nitrogen fixation.
Published: 2023

45. Features of Mycobacterium bovis Complete Genomes Belonging to 5 Different Lineages

Author: Ciriac Charles, Cyril Conde, Fabien Vorimore, Thierry Cochard, Lorraine Michelet, Maria Laura Boschiroli, Franck Biet, Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Laboratoire de sécurité des aliments de Maisons-Alfort (LSAl), Unité Zoonoses Bactériennes (UZB), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), ANSES, and European Project: 773830, H2020-SFS-2017-1 ,One Health EJP(2018)
Subjects: Microbiology (medical), pangenome, mammalian tuberculosis (TB), Virology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], transmission, complete de novo assembly, Mycobacterium bovis, Microbiology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: Publication on Microorganisms. 11 January 2023. https://www.mdpi.com/2076-2607/11/1/177 Abstract: Mammalian tuberculosis (TB) is a zoonotic disease mainly due toMycobacterium bovis(M. bovis). A current challenge for its eradication is understanding its transmission within multi-host systems. Improvements in long-read sequencing technologies have made it possible to obtain complete bacterial genomes that provide a comprehensive view of species-specific genomic features. In the context of TB, new genomic references based on complete genomes genetically close to field strains are also essential to perform precise field molecular epidemiological studies. A total of 10M. bovisstrains representing each genetic lineage identified in France and in other countries were selected for performing complete assembly of their genomes. Pangenome analysis revealed a “closed” pangenome composed of 3900 core genes and only 96 accessory genes. Whole genomes-based alignment using progressive Mauve showed remarkable conservation of the genomic synteny except that the genomes have a variable number of copies of IS6110. Characteristic genomic traits of each lineage were identified through the discovery of specific indels. Altogether, these results provide new genetic features that improve the description ofM. bovislineages. The availability of new complete representative genomes ofM. boviswill be useful to epidemiological studies and better understand the transmission of this clonal-evolving pathogen.
Published: 2023
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46. Chemically diverse activity-based probes with unexpected inhibitory mechanisms targeting trypsin-like serine proteases

Author: Alba Ramos-Llorca, Lisse Decraecker, Valérie M. Y. Cacheux, Irena Zeiburlina, Michelle De bruyn, Louise Battut, Carlos Moreno-Cinos, Davide Ceradini, Eric Espinosa, Gilles Dietrich, Maya Berg, Ingrid De Meester, Pieter Van Der Veken, Guy Boeckxstaens, Anne-Marie Lambeir, Alexandre Denadai-Souza, Koen Augustyns, University of Antwerp (UA), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), 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), Latvian Institute of Organic Synthesis [Riga, Lituania], Research Fund Flanders grant agreement FWO-SBO S 001017, the University of Antwerp SEP-BOF grant number 44875, and European Project
Subjects: mast cells (MCs), Chemistry, serine protease, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pharmacology. Therapy, inhibitors, activity-based probe, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, General Chemistry, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, irreversible inhibition
Abstract: Activity-based probes (ABP) are molecules that bind covalently to the active form of an enzyme family, making them an attractive tool for target and biomarker identification and drug discovery. The present study describes the synthesis and biochemical characterization of novel activity-based probes targeting trypsin-like serine proteases. We developed an extensive library of activity-based probes with "clickable" affinity tags and a diaryl phosphonate warhead. A wide diversity was achieved by including natural amino acid analogs as well as basic polar residues as side chains. A detailed enzymatic characterization was performed in a panel of trypsin-like serine proteases. Their inhibitory potencies and kinetic profile were examined, and their IC50 values, mechanism of inhibition, and kinetic constants were determined. The activity-based probes with a benzyl guanidine side chain showed the highest inhibitory effects in the panel. Surprisingly, some of the high-affinity probes presented a reversible inhibitory mechanism. On the other hand, probes with different side chains exhibited the expected irreversible mechanism. For the first time, we demonstrate that not only irreversible probes but also reversible probes can tightly label recombinant proteases and proteases released from human mast cells. Even under denaturing SDS-PAGE conditions, reversible slow-tight-binding probes can label proteases due to the formation of high-affinity complexes and slow dissociation rates. This unexpected finding will transform the view on the required irreversible nature of activity-based probes. The diversity of this library of activity-based probes combined with a detailed enzyme kinetic characterization will advance their applications in proteomic studies and drug discovery. ispartof: FRONTIERS IN CHEMISTRY vol:10 ispartof: location:Switzerland status: published
Published: 2023

47. Circovirus Hepatitis Infection in Heart-Lung Transplant Patient, France

Author: Philippe Pérot, Jacques Fourgeaud, Claire Rouzaud, Béatrice Regnault, Nicolas Da Rocha, Hélène Fontaine, Jérôme Le Pavec, Samuel Dolidon, Margaux Garzaro, Delphine Chrétien, Guillaume Morcrette, Thierry Jo Molina, Agnès Ferroni, Marianne Leruez-Ville, Olivier Lortholary, Anne Jamet, Marc Eloit, Centre Collaborateur de l'OIE de Détection et identification chez l’homme des pathogènes animaux émergents et développement d’outils pour leur diagnostic / Collaborating Center for the Detection and identification in humans of emerging animal pathogens and development of tools for their diagnoses (CCOIE-OIECC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé Animale / World Organisation Animal Health [Paris] (OIE)-Université Paris Cité (UPCité), Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Groupe Hospitalier Paris Saint-Joseph (hpsj), Hôpital Cochin [AP-HP], Université Paris-Sud - Paris 11 (UP11), Hôpital Marie-Lannelongue, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École nationale vétérinaire - Alfort (ENVA), and This work was supported by Institut Pasteur and the Necker-Enfants malades University Hospital.
Subjects: Microbiology (medical), Epidemiology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, metagenomic next-generation sequencing, zoonoses, Infectious Diseases, mNGS, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], circoviruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, hepatitis, solid organ transplants, viruses, France
Abstract: International audience; In March 2022, a 61-year-old woman in France who had received a heart-lung transplant sought treatment with chronic hepatitis mainly characterized by increased liver enzymes. After ruling out common etiologies, we used metagenomic next-generation sequencing to analyze a liver biopsy sample and identified an unknown species of circovirus, tentatively named human circovirus 1 (HCirV-1). We found no other viral or bacterial sequences. HCirV-1 shared 70% amino acid identity with the closest known viral sequences. The viral genome was undetectable in blood samples from 2017–2019, then became detectable at low levels in September 2020 and peaked at very high titers (10^10 genome copies/mL) in January 2022. In March 2022, we found >10^8 genome copies/g or mL in the liver and blood, concomitant with hepatic cytolysis. We detected HCirV-1 transcripts in 2% of hepatocytes, demonstrating viral replication and supporting the role of HCirV-1 in liver damage.
Published: 2023

48. RSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells

Author: Sébastien Durand, Marion Bruelle, Fleur Bourdelais, Bigitha Bennychen, Juliana Blin-Gonthier, Caroline Isaac, Aurélia Huyghe, Sylvie Martel, Antoine Seyve, Christophe Vanbelle, Annie Adrait, Yohann Couté, David Meyronet, Frédéric Catez, Jean-Jacques Diaz, Fabrice Lavial, Emiliano P. Ricci, François Ducray, Mathieu Gabut, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Hospices Civils de Lyon (HCL), Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)
Subjects: Multidisciplinary, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], General Physics and Astronomy, General Chemistry, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], General Biochemistry, Genetics and Molecular Biology
Abstract: Embryonic stem cell (ESC) fate decisions are regulated by a complex circuitry that coordinates gene expression at multiple levels from chromatin to mRNA processing. Recently, ribosome biogenesis and translation have emerged as key pathways that efficiently control stem cell homeostasis, yet the underlying molecular mechanisms remain largely unknown. Here, we identified RSL24D1 as highly expressed in both mouse and human pluripotent stem cells. RSL24D1 is associated with nuclear pre-ribosomes and is required for the biogenesis of 60S subunits in mouse ESCs. Interestingly, RSL24D1 depletion significantly impairs global translation, particularly of key pluripotency factors and of components from the Polycomb Repressive Complex 2 (PRC2). While having a moderate impact on differentiation, RSL24D1 depletion significantly alters ESC self-renewal and lineage commitment choices. Altogether, these results demonstrate that RSL24D1-dependant ribosome biogenesis is both required to sustain the expression of pluripotent transcriptional programs and to silence PRC2-regulated developmental programs, which concertedly dictate ESC homeostasis.
Published: 2023

49. The histone methyltransferase DOT1L regulates chromatin reorganization and gene expression during the postmeiotic differentiation of male germ cells

Author: Blanco, Mélina, Khattabi, Laila El, Gobé, Clara, Crespo, Marion, Coulée, Manon, de la Iglesia, Alberto, Ialy-Radio, Côme, Lapoujade, Clementine, Givelet, Maëlle, Delessard, Marion, Seller-Corona, Ivan, Yamaguchi, Kosuke, Vernet, Nadège, van Leeuwen, Fred, Lermine, Alban, Okada, Yuki, Daveau, Romain, Oliva, Rafael, Fouchet, Pierre, Ziyyat, Ahmed, Pflieger, Delphine, Cocquet, Julie, 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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), 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 Grenoble Alpes (UGA), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, The University of Tokyo (UTokyo), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Cochin [AP-HP], ANR-17-CE12-0004,CHROMATOZOA,(Dé)régulation génique et chromatinienne pendant la spermiogénèse: acteurs & conséquences sur la descendance(2017), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), PFLIEGER, Delphine, (Dé)régulation génique et chromatinienne pendant la spermiogénèse: acteurs & conséquences sur la descendance - - CHROMATOZOA2017 - ANR-17-CE12-0004 - AAPG2017 - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID
Subjects: histone-to-protamine replacement, chromatin compaction, flagellum development, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], DOT1L, H3K79 methylation, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], gene regulation, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], spermatogenesis, [SDV.BDD.GAM]Life Sciences [q-bio]/Development Biology/Gametogenesis
Abstract: International audience; Spermatozoa have a unique genome organization: their chromatin is almost completely devoid of histones and is formed instead of protamines which confer a higher level of compaction than nucleosomes and preserve paternal genome integrity until fertilization. Histone-to-protamine transition takes place in postmeiotic male germ cells called spermatids, and is indispensable for the production of functional spermatozoa and thus for male fertility. Here we show that the H3K79 (histone 3 lysine 79) methyltransferase DOT1L controls spermatid chromatin remodelling and subsequent reorganization and compaction of spermatozoon genome. Using a mouse model in which Dot1l is knocked-out in adult male germ cells, we found that the chromatin of Dot1l -knockout (KO) spermatozoa is less compact and characterized by a higher level of retained histones and of immature forms of protamine 2. Proteomic analyses performed on differentiating male germ cells reveal that Dot1l KO extensively modifies the spermatid chromatin prior to histone removal. By transcriptomics, we also show that Dot1l KO deregulates the expression of ~1500 genes, many of which are involved in other essential aspects of spermatid differentiation such as flagellum formation. As a consequence of all these chromatin and gene expression defects, Dot1l -KO spermatozoa have misshapen and less compact heads, and are less motile, which results in impaired fertility.
Published: 2023

50. Molecular characterization of accripin11, a soluble shell protein with an acidic C‐terminus, identified in the prismatic layer of the Mediterranean fan mussel Pinna nobilis (Bivalvia, Pteriomorphia)

Author: Benazir, Khurshid, Daniel J, Jackson, Sylvain, Engilberge, Sébastien, Motreuil, Cédric, Broussard, Jérôme, Thomas, Françoise, Immel, Matthew J, Harrington, Peter B, Crowley, Daniel, Vielzeuf, Jonathan, Perrin, Frédéric, Marin, Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Structural Biology Group (SB Group), European Synchroton Radiation Facility [Grenoble] (ESRF), Plateforme protéomique 3P5 [Institut Cochin] (3P5), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), While the beginnings of this work were financed by anACI 'jeunes chercheurs' program (ACI JC 3049, FM)and by the ITN BioMintec (FM), the main body of thestudy has been financially supported by ANR MOBi22 FEBS Open Bio 13 (2023) 10–25 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf ofFederation of European Biochemical Societies.Structure of a mollusk shell protein B. Khurshid et al.22115463, 2023, 1, Downloaded from https://febs.onlinelibrary.wiley.com/doi/10.1002/2211-5463.13497 by Cochrane France, Wiley Online Library on [03/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use, OA articles are governed by the applicable Creative Commons License(ANR-18-CE02-0014-02, 2018-2023), including the salaryof B. Kurshid and most of the consumables andchemicals. The overexpression work on accripin11 wassupported by IABECA program (2014–2015) of theUniv. Burgundy (FI, FM). Other financial supportsinclude (a) the Research Project of Excellence BFC'PIA-Recolnat-BFC' supported by region Burgundy –Franche-Comte and the 'Recolnat ANR-11-INBS-0004' program for proteomics (JT), (b) the SRO'Pinocchio' project (PInna NObilis & sa CalcificationCoquilliere: une Histoire Originale, FM) of OSU-Theta(Bourgogne – Franche-Comte), (c) the EMBRC (EuropeanMarine Biological Resource Centre, FM), whichprovided the logistic support for a field mission to collectliving specimens of P. nobilis at Villefranche-sur-Mer marine station in spring 2017, and (d) grants fromthe Max Planck Society, the Deutsche Forschungsgemeinschaft(DFG) (HA6369/4-1 and JA 2108/6-1) andthe Natural Sciences and Engineering Research Councilof Canada (NSERC Discovery Grant RGPIN-2018-05243) for the acquisition of the transcriptome of P. nobilis(MJH)., ANR-18-CE02-0014,MOBi,Interface Organique/Inorganique dans les Biominéraux(2018), ANR-11-INBS-0004,E-RECOLNAT,Valorisation de 350 ans de collections d'histoire naturelle : une plateforme numérique(2011), Laffont, Rémi, APPEL À PROJETS GÉNÉRIQUE 2018 - Interface Organique/Inorganique dans les Biominéraux - - MOBi2018 - ANR-18-CE02-0014 - AAPG2018 - VALID, and Infrastructures - Valorisation de 350 ans de collections d'histoire naturelle : une plateforme numérique - - E-RECOLNAT2011 - ANR-11-INBS-0004 - INBS - VALID
Subjects: Proteomics, Aspartic Acid, Proteins, calcitic prisms, Bivalvia, Calcium Carbonate, [SDV.BA.ZI]Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, biomineral, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BA.ZI] Life Sciences [q-bio]/Animal biology/Invertebrate Zoology, mollusc shell, Animals, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], protein, Alphafold2
Abstract: International audience; We have identified a novel shell protein, accripin11, as a major soluble component of the calcitic prisms of the fan mussel Pinna nobilis. Initially retrieved from a cDNA library, its full sequence is confirmed here by transcriptomic and proteomic approaches. The sequence of the mature protein is 103 residues with a theoretical molecular weight of 11 kDa and is moderately acidic (pI 6.74) except for its C-terminus which is highly enriched in aspartic acid. The protein exhibits a peculiar cysteine pattern in its central domain. The full sequence shares similarity with six other uncharacterized molluscan shell proteins from the orders Ostreida, Pteriida and Mytilida, all of which are pteriomorphids and produce a phylogenetically restricted pattern of nacro-prismatic shell microstructures. This suggests that accripin11 is a member of a family of clade-specific shell proteins. A 3D model of accripin11 was predicted with AlphaFold2, indicating that it possesses 3 short alpha helices and a disordered C-terminus. Recombinant accripin11 was tested in vitro for its ability to influence the crystallization of CaCO3, while a polyclonal antibody was able to locate accripin11 to prismatic extracts, particularly in the acetic acid-soluble matrix. The putative functions of accripin11 are further discussed in relation to shell biomineralization.
Published: 2023

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