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1. Apport de la génomique dans la médecine de demain, applications cliniques et enjeux

Author

Lionel Perrier, Guillaume Grenet, Bruno Laviolle, Florence Gaillard-Bigot, Pascal Bilbault, Olivier Perche, Hélène Espérou, Jean-François Guérin, Julia Morere, Julien Thevenon, Caroline Guillot, Élodie Bégué, François Gueyffier, Damien Sanlaville, Pierre-Henry Longeray, Nathalie Varoqueaux, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC CHU Lyon (inserm), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine Laennec, Université de Lyon, Lyon, France., Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), The Lymphoma Academic Research Organisation [Lyon] (LYSARC), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Hospices Civils de Lyon, Departement de Neurologie (HCL), Pfizer Oncology, Fédération française des diabétiques, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Groupe d'Analyse et de Théorie Economique Lyon - Saint-Etienne (GATE Lyon Saint-Étienne), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre hospitalier universitaire de Grenoble (CHU de Grenoble), CHU Grenoble, Roche SAS, Neuilly-sur-Seine, France, Laboratoire Roche SAS, AstraZeneca, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Ligue Nationnale Contre le Cancer, Hypoxie et physiopathologies cardiovasculaire et respiratoire, Groupe d'analyse et de théorie économique (GATE Lyon Saint-Étienne), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Claude Bernard Lyon 1 (UCBL), and Dao, Taï

Subjects
Thérapeutique, [QFIN]Quantitative Finance [q-fin], [SDV]Life Sciences [q-bio], Questions éthiques, Médecine personnalisée, 030226 pharmacology & pharmacy, [QFIN] Quantitative Finance [q-fin], Séquençage du génome entier, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Pronostic, Pharmacology (medical), Diagnostic
Abstract

International audience; Le séquençage du génome est aujourd’hui accessible à la population mais il n’existe que peu de preuves de son utilité comme outil diagnostique, thérapeutique et pronostique. En France, le plan France médecine génomique 2025 a été lancé en 2015 avec pour objectif d’intégrer les analyses génomiques dans la pratique clinique pour des indications validées et de développer une filière nationale de la médecine génomique incluant des partenariats industriels. Une réflexion sur les applications scientifiques et les enjeux opérationnels et sociétaux est nécessaire afin de formuler des recommandations pour permettre de mieux associer la génomique et la médecine de demain. Dans la perspective d’une médecine factuelle personnalisée, il convient de promouvoir des études avec un niveau d’exigence méthodologique approprié et d’approfondir la définition du niveau de preuve. Les nombreux enjeux opérationnels nécessitent de mettre en place des organisations et des moyens afin de fluidifier le circuit de rendu des résultats ainsi que des adaptations réglementaires sur les statuts des professions impliquées, la gestion des données générées et le consentement des patients. En parallèle des actions de formation en génétique à destination des professionnels de santé et des actions de sensibilisation sur les tests génétiques vis-à-vis du grand public doivent être envisagées. Les enjeux éthiques doivent également être pris en compte, notamment sur la participation du patient aux décisions le concernant en fonction de ses attentes et en intégrant la notion d’incertitude dans l’information délivrée. Les effets sociologiques sur le vécu et les attentes des patients et de la population générale vis-à-vis de la médecine génomique doivent également être évalués pour améliorer l’information, la prévention et l’accompagnement des personnes. Enfin, des études médicoéconomiques doivent être conduites pour éclairer les décideurs sur le caractère coût-efficace du séquençage complet du génome pour la santé des populations.

Published
2019
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2. Analysis of the 4q35 chromatin organization reveals distinct long-range interactions in patients affected with Facio-Scapulo-Humeral Dystrophy

Author

Camille Laberthonnière, Marie-Cécile Gaillard, Natacha Broucqsault, Cherif Badja, Stéphane Roche, Jérôme D. Robin, Julia Morere, Karine Nguyen, Frédérique Magdinier, Camille Dion, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Chromosomal Proteins, Non-Histone, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Gene Expression, lcsh:Medicine, Diseases, Pathogenesis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], 0302 clinical medicine, Gene expression, lcsh:Science, In Situ Hybridization, Fluorescence, Genetics, 0303 health sciences, Middle Aged, Cadherins, Subtelomere, Chromatin, Muscular Dystrophy, Facioscapulohumeral, Epigenetics, Female, Chromosomes, Human, Pair 4, Adult, Adolescent, Induced Pluripotent Stem Cells, Locus (genetics), Biology, Chromatin structure, Article, Young Adult, 03 medical and health sciences, Imaging, Three-Dimensional, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Muscle, Skeletal, Gene, Aged, 030304 developmental biology, lcsh:R, Infant, Dystrophy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Fibroblasts, Chromosome 4, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Case-Control Studies, Mutation, lcsh:Q, 030217 neurology & neurosurgery
Abstract

International audience; 1 Facio-Scapulo Humeral dystrophy (FSHD) is the third most common myopathy, affecting 1 amongst 10,000 individuals (FSHD1, OMIM #158900). This autosomal dominant pathology is associated in 95% of cases with genetic and epigenetic alterations in the subtelomeric region at the extremity of the long arm of chromosome 4 (q arm). A large proportion of the remaining 5% of cases carry a mutation in the SMCHD1 gene (FSHD2, OMIM #158901). Here, we explored the 3D organization of the 4q35 locus by three-dimensions DNA in situ fluorescent hybridization (3D-FISH) in primary fibroblasts isolated from patients and healthy donors. We found that D4Z4 contractions and/or SMCHD1 mutations impact the spatial organization of the 4q35 region and trigger changes in the expression of different genes. Changes in gene expression were corroborated in muscle biopsies suggesting that the modified chromatin landscape impelled a modulation in the level of expression of a number of genes across the 4q35 locus in FSHD. Using induced pluripotent stem cells (hIPSC), we further examined whether chromatin organization is inherited after reprogramming or acquired during differentiation and showed that folding of the 4q35 region is modified upon differentiation. These results together with previous findings highlight the role of the D4Z4 macrosatellite repeat in the topological organization of chromatin and further indicate that the D4Z4-dependent 3D structure induces transcriptional changes of 4q35 genes expression.

Published
2019
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3. The contribution of genomics in the medicine of tomorrow, clinical applications and issues

Author

Florence Gaillard-Bigot, Patrice Denèfle, Nathalie Varoqueaux, Damien Sanlaville, Jean-François Guérin, Lionel Perrier, Olivier Perche, Julia Morere, Caroline Guillot, Pascal Bilbault, François Gueyffier, Pierre-Henry Longeray, Guillaume Grenet, Élodie Bégué, Bruno Laviolle, Julien Thevenon, Hélène Espérou, Service de Pharmacologie [Rennes], CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Généthon, Evaluation et modélisation des effets thérapeutiques, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], 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)-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)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), 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), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Les Hôpitaux Universitaires de Strasbourg (HUS), Agence de la biomédecine [Saint-Denis la Plaine], Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Hospices Civils de Lyon (HCL), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération française des diabétiques, Centre Hospitalier Régional d'Orléans (CHRO), Centre Léon Bérard [Lyon], Groupe d'Analyse et de Théorie Economique Lyon - Saint-Etienne (GATE Lyon Saint-Étienne), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Service de Cytogénétique (HFME), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Roche SAS, Neuilly-sur-Seine, France, Laboratoire Roche SAS, The advent of a new paradigm induced by the massive deployment of high-throughput sequencing raises economic and organisational issues. The evaluation of the production cost of genome sequences shows a notable change in the production costs of a gene panel targeted by next-generation sequencing (NGS) according to indications, enrichment techniques, retained sequencing, or the number of patients per run. In France, for example, the cost per patient (from the receipt of samples to the return of results to prescribers) varies from one to three depending on the laboratories [17]. What about the cost of genome sequencing? One can assume that production costs will largely depend on the organisational model chosen and its ability to integrate multiple technical constraints (prescription portals, automated extraction systems, production platform, IT infrastructure, data analysis, rendering of results, interoperability with patient records, etc.).The medico-economic assessment of the genome-wide sequencing strategy is essential to inform policy makers on the cost-effectiveness (or not) of one or more innovative health strategies compared to the reference strategy (s). These assessments are planned in the pilot projects of the France genomics 2025 plan. This approach has well-known benefits such as the absence (most often) of selection bias. In contrast, the time horizon of the economic evaluation is usually limited to the follow-up period of the trial and differential cost-result ratio (DCRR) is not always expressed in cost per year of life gained in good health. These can also emanate from modelling. The review of the literature published by Schwarze et al. on genome sequencing reports a very limited number (N = 8) of publications including a complete medico-economic assessment (i.e. that integrates economic considerations and clinical efficacy) [18]. Furthermore, the heterogeneity of the efficacy criteria does not favour comparisons between studies. Only one of them expresses the DCRR in cost per year of life gained in good health [19]., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Roche, Université de Lyon, Ligue Nationnale Contre le Cancer, Hypoxie et physiopathologies cardiovasculaire et respiratoire, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'analyse et de théorie économique (GATE Lyon Saint-Étienne), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), Dao, Taï, and École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
Big Data, Process (engineering), [SDV]Life Sciences [q-bio], Commodity, Population, education, Genomics, Population health, Therapeutics, Social issues, 030226 pharmacology & pharmacy, [SHS]Humanities and Social Sciences, Translational Research, Biomedical, 03 medical and health sciences, 0302 clinical medicine, Diagnosis, Humans, Genomic medicine, Pharmacology (medical), Precision Medicine, education.field_of_study, Evidence-Based Medicine, business.industry, Ethical issues, Prognosis, Personalized medicine, 3. Good health, [SDV] Life Sciences [q-bio], Whole genome sequencing, Engineering ethics, France, [SHS] Humanities and Social Sciences, business
Abstract

International audience; Fifteen years after the completion of first human genome sequencing, the technique is almost a commodity but there is still little evidence of its usefulness as a diagnostic, prognostic or therapeutic tool. In France, the France genomics plan 2025 was launched in 2015 with the goal of integrating genomic tests into clinical practice and developing a National genomics network including industrial partnerships. Reflection on scientific applications and operational or societal issues is needed to make recommendations to help better associate Genomics and the medicine of tomorrow. In the perspective of personalized Evidence-based Medicine, studies with an appropriate methodological level to improve the definition of evidence should be promoted. The many operational challenges require the implementation of organisations and means to streamline the process of results reporting, and regulatory adaptations concerning the status of professions involved, the management of data generated, and the consent of patients. In parallel, genetic training for healthcare professionals and raising awareness on genetic tests for the public should be considered. The ethical stake should also be taken into account, especially on the participation of the patient in decisions concerning them and integrating the notion of uncertainty into the information given. The sociological effects on the experience and expectations of patients and the general population towards genomic medicine should also be evaluated to improve information, prevention and support for people. Finally, medico-economic studies must be conducted to inform policy-makers on the cost-effectiveness of complete genome sequencing for population health.

Published
2019
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4. TRF2 and Apollo Cooperate with Topoisomerase 2α to Protect Human Telomeres from Replicative Damage

Author

Annamaria Biroccio, Eric Gilson, Anaïs Poulet, Christelle Lenain, Anna Bizard, Delphine Benarroch, Arturo Londoño-Vallejo, Erica Salvati, Laure Sabatier, Els Verhoeyen, Julia Morere, Jing Ye, Sébastien Britton, Bernard Salles, Yunlin Wu, Angela Maria Rizzo, Marc Nadal, Patrick Calsou, Adelaïde Saint-Léger, Marie Josèphe Giraud-Panis, Frédérique Magdinier, Simon Amiard, Serge Bauwens, Shanghai Jiao Tong University School of Medicine, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), 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), Laboratoire de biologie et pathologie des génomes, Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Chemotherapy Laboratory, Regina Elena Cancer Institute, Laboratoire Joliot Curie, École normale supérieure de Lyon (ENS de Lyon)-Centre National de la Recherche Scientifique (CNRS), Virologie humaine, École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Radiobiologie et d'Oncologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Department of Medical Genetics, Centre Hospitalier Universitaire de Nice (CHU Nice), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratory of Biology and Pathology of Genomes, Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Nice Sophia Antipolis (... - 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 École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
[SDV]Life Sciences [q-bio], MESH: Antigens, Neoplasm, MESH: DNA Replication, chemistry.chemical_compound, MESH: Protein Structure, Tertiary, 0302 clinical medicine, Telomeric Repeat Binding Protein 2, ComputingMilieux_MISCELLANEOUS, Cellular Senescence, Genetics, Telomere-binding protein, 0303 health sciences, Nuclear Proteins, MESH: Telomeric Repeat Binding Protein 2, Telomere, DNA-Binding Proteins, MESH: DNA Repair Enzymes, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, MESH: Cell Aging, 030220 oncology & carcinogenesis, DNA supercoil, Cell aging, DNA Replication, DNA damage, DNA repair, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Antigens, Neoplasm, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, MESH: DNA Topoisomerases, Type II, Eukaryotic, MESH: DNA Damage, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), DNA replication, DNA, Protein Structure, Tertiary, DNA Repair Enzymes, DNA Topoisomerases, Type II, Exodeoxyribonucleases, chemistry, MESH: Telomere, MESH: Nuclear Proteins, MESH: DNA-Binding Proteins, DNA Damage
Abstract

International audience; Human telomeres are protected from DNA damage by a nucleoprotein complex that includes the repeat-binding factor TRF2. Here, we report that TRF2 regulates the 5' exonuclease activity of its binding partner, Apollo, a member of the metallo-beta-lactamase family that is required for telomere integrity during S phase. TRF2 and Apollo also suppress damage to engineered interstitial telomere repeat tracts that were inserted far away from chromosome ends. Genetic data indicate that DNA topoisomerase 2alpha acts in the same pathway of telomere protection as TRF2 and Apollo. Moreover, TRF2, which binds preferentially to positively supercoiled DNA substrates, together with Apollo, negatively regulates the amount of TOP1, TOP2alpha, and TOP2beta at telomeres. Our data are consistent with a model in which TRF2 and Apollo relieve topological stress during telomere replication. Our work also suggests that cellular senescence may be caused by topological problems that occur during the replication of the inner portion of telomeres.

Published
2010
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5. Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers

Author

Frédérique Magdinier, Rafaëlle Bernard, Stéphane Roche, Emmanuelle Salort-Campana, Natacha Broucqsault, Julia Morere, Marie-Cécile Gaillard, Karine Nguyen, Marc Bartoli, Camille Dion, Nicolas Lévy, Armand Tasmadjian, Francesca Puppo, Catherine Vovan, Gwenaëlle Bouget, Charlene Chaix, Shahram Attarian, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-09-GENO-0038,FSHDecrypt,Analyse à grande échelle de la région 4qTer : décodage génétique et épigénétique du locus de la dystrophie musculaire Facio-Scapulo-Humérale(2009), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Bartoli, Marc, and Physiopathologie moléculaire: des maladies rares aux maladies communes - Analyse à grande échelle de la région 4qTer : décodage génétique et épigénétique du locus de la dystrophie musculaire Facio-Scapulo-Humérale - - FSHDecrypt2009 - ANR-09-GENO-0038 - GENO - VALID

Subjects
Male, Oncology, Pathology, Penetrance, Epigenesis, Genetic, 0302 clinical medicine, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, DNA methylation, Bisulfite, Methylation, Muscular Dystrophy, Facioscapulohumeral, Pedigree, 3. Good health, Phenotype, Female, Epigenetics, Chromosomes, Human, Pair 4, medicine.symptom, Adult, musculoskeletal diseases, Heterozygote, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Asymptomatic, MeDIP, Young Adult, 03 medical and health sciences, Internal medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Testing, Methylated DNA immunoprecipitation, 030304 developmental biology, FSHD, D4Z4, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurology (clinical), Asymptomatic carrier, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, DNA hypomethylation
Abstract

International audience; Objective: We investigated the link between DNA hypomethylation and clinical penetrance in facioscapulohumeral dystrophy (FSHD) because hypomethylation is moderate and heterogeneous in patients and could not thus far be correlated with disease presence or severity. Methods: To investigate the link between clinical signs of FSHD and DNA methylation, we explored 95 cases (37 FSHD1, 29 asymptomatic individuals carrying a shortened D4Z4 array, 9 patients with FSHD2, and 20 controls) by implementing 2 approaches: methylated DNA immunoprecipitation and sodium bisulfite sequencing. Results: Both methods revealed statistically significant differences between asymptomatic carriers or controls and individuals with clinical FSHD, especially in the proximal region of the repeat. Absence of clinical expression in asymptomatic carriers is associated with a level of methylation similar to controls. Conclusions: We provide a proof of concept that the targeted approaches that we describe could be applied systematically to patient samples in routine diagnosis and suggest that local hypomethylation within D4Z4 might serve as a modifier for clinical expression of FSHD phenotype. Classification of evidence: This study provides Class III evidence that assays for hypomethylation within the D4Z4 region accurately distinguish patients with FSHD from individuals with D4Z4 contraction without FSHD.

Published
2014
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6. Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Author

Paula Frizera, Vassallo, Stéphanie, Simoncini, Isabelle, Ligi, Anne-Line, Chateau, Richard, Bachelier, Stéphane, Robert, Julia, Morere, Samantha, Fernandez, Benjamin, Guillet, Maxime, Marcelli, Edwige, Tellier, Alain, Pascal, Umberto, Simeoni, Francine, Anfosso, Frédérique, Magdinier, Françoise, Dignat-George, and Florence, Sabatier

Subjects
Sirtuin 1, Stress, Physiological, Case-Control Studies, Infant, Newborn, Down-Regulation, Endothelial Cells, Humans, Premature Birth, Fetal Blood, Hematopoietic Stem Cells, Cells, Cultured, Cellular Senescence, Infant, Premature
Abstract

Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic activity of endothelial colony-forming cells (ECFCs) in this condition. We hypothesized that ECFC dysfunction in PT might result from premature senescence and investigated the underlying mechanisms. Compared with ECFCs from term neonates (n = 18), ECFCs isolated from PT (n = 29) display an accelerated senescence sustained by growth arrest and increased senescence-associated β-galactosidase activity. Increased p16(INK4a) expression, in the absence of telomere shortening, indicates that premature PT-ECFC aging results from stress-induced senescence. SIRT1 level, a nicotinamide adenine dinucleotide-dependent deacetylase with anti-aging activities, is dramatically decreased in PT-ECFCs and correlated with gestational age. SIRT1 deficiency is subsequent to epigenetic silencing of its promoter. Transient SIRT1 overexpression or chemical induction by resveratrol treatment reverses senescence phenotype, and rescues in vitro PT-ECFC angiogenic defect in a SIRT1-dependent manner. SIRT1 overexpression also restores PT-ECFC capacity for neovessel formation in vivo. We thus demonstrate that decreased expression of SIRT1 drives accelerated senescence of PT-ECFCs, and acts as a critical determinant of the PT-ECFC angiogenic defect. These findings lay new grounds for understanding the increased cardiovascular risk in individuals born prematurely and open perspectives for therapeutic strategy.

Published
2014

7. Dysregulation of 4q35- and muscle-specific genes in fetuses with a short D4Z4 array linked to facio-scapulo-humeral dystrophy

Author

André Maues De Paula, Stéphane Roche, Julia Torrents, Marie Cécile Gaillard, Frédérique Magdinier, Henry Dufour, Natacha Broucqsault, Claude Desnuelle, Laure Sarda, Marc Bartoli, Carla Fernandez, Emmanuelle Salort-Campana, Karine Nguyen, Julie Dumonceaux, Anne Laure Chesnais, Julia Morere, Maxime Ferreboeuf, Shahram Attarian, Nicolas Lévy, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Anatomie et Cytologie Pathologiques, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de néphrologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lattice - Langues, Textes, Traitements informatiques, Cognition - UMR 8094 (Lattice), Université Sorbonne Nouvelle - Paris 3-Université Sorbonne Paris Cité (USPC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris sciences et lettres (PSL)-Département Littératures et langage - ENS Paris (LILA), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL), Service de neurochirurgie [CHU Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de signalisation, biologie du développement et cancer (ISBDC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Département Littératures et langage - ENS Paris (LILA), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Sorbonne Paris Cité (USPC)-Université Sorbonne Nouvelle - Paris 3, Service de neurochirurgie, Université Nice Sophia Antipolis (... - 2019) (UNS), Département Littératures et langage (LILA), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
musculoskeletal diseases, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Develoment, DUX4, Locus (genetics), Penetrance, Biology, Muscle Development, 03 medical and health sciences, 0302 clinical medicine, Fetus, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Facioscapulohumeral muscular dystrophy, Humans, Muscular dystrophy, Molecular Biology, Genetics (clinical), 030304 developmental biology, MyoD Protein, Repetitive Sequences, Nucleic Acid, Homeodomain Proteins, 0303 health sciences, FSHD, D4Z4, Myogenesis, Dystrophy, Gene Expression Regulation, Developmental, Cell Differentiation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, medicine.disease, Subtelomere, Muscular Dystrophy, Facioscapulohumeral, MYOD1, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Organ Specificity, Case-Control Studies, Muscle, Chromosomes, Human, Pair 4, 030217 neurology & neurosurgery
Abstract

International audience; Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD pathophysiology. However, no one knows what triggers muscle defect and when alteration arises. To gain further insights into the molecular mechanisms of the disease, we evaluated at the molecular level, the perturbation linked to the FSHD genotype with no a priori on disease onset, severity or penetrance and prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses carrying a short pathogenic D4Z4 array (n 5 6) compared with fetuses with a non-pathogenic D4Z4 array (n 5 21). By measuring expression of several muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR and western blotting, we observed a global dysregulation of genes involved in myogenesis including MYOD1 in samples with

Published
2013
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8. DUX4 and DUX4 downstream target genes are expressed in fetal FSHD muscles

Author

Sophie Collardeau, Julia Morere, Virginie Mariot, Stéphane Roche, Vincent Mouly, Julie Dumonceaux, Sandra Whalen, Frédérique Magdinier, Bettina Bessières, Philippe Rameau, Alexandre Vasiljevic, Tania Attié-Bitach, Claude Desnuelle, Jérôme Robin-Ducellier, Gillian Butler-Browne, Maxime Ferreboeuf, Sabrina Sacconi, Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 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), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and RUIZ, Caroline

Subjects
Male, Pathology, DUX4, Muscle Fibers, Skeletal, Muscle Development, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Quadriceps Muscle, 0302 clinical medicine, RNA Isoforms, Protein Isoforms, Facioscapulohumeral muscular dystrophy, RNA, Small Interfering, Muscular dystrophy, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Cells, Cultured, Genetics (clinical), Regulation of gene expression, 0303 health sciences, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, Myogenesis, Gene Expression Regulation, Developmental, General Medicine, Middle Aged, Muscular Dystrophy, Facioscapulohumeral, 3. Good health, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Muscle, Female, Adult, Gene isoform, medicine.medical_specialty, Biology, 03 medical and health sciences, Fetus, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BDD] Life Sciences [q-bio]/Development Biology, Biopsy, Genetics, medicine, Humans, Molecular Biology, 030304 developmental biology, Homeodomain Proteins, FSHD, Molecular markers, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biomarker, medicine.disease, Molecular biology, Repressor Proteins, Superficial Back Muscles, 030217 neurology & neurosurgery
Abstract

International audience; : Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregulations can be identified during FSHD fetal muscle development. We compared muscle biopsies derived from FSHD1 fetuses and the cells derived from some of these biopsies with biopsies and cells derived from control fetuses. We mainly focus on DUX4 isoform expression because the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. We measured DUX4 isoform expression by using qRT-PCR in fetal FSHD1 myotubes treated or not with an shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream target gene expression in myotubes and fetal or adult FSHD1 and control quadriceps biopsies. We show that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes. We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD1 fetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during fetal life, thus opening a new field of investigation for mechanisms leading to FSHD.

Published
2013
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9. Identification of a perinuclear positioning element in human subtelomeres that requires A-type lamins and CTCF

Author

Frédérique Magdinier, Serge Bauwens, Eric Gilson, Alexandre Ottaviani, Sophie Gazzo, Sylvie Rival-Gervier, Julia Morere, Evelyne Callet-Bauchu, Amina Boussouar, Delphine Rondier, Caroline Schluth-Bolard, Andrea M. Foerster, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Génétique Médicale et Génomique Fonctionnelle (GMGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 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 d'Hématologie, Hospices Civils de Lyon (HCL), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Lyon (ENS 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), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Biologie du Développement et Reproduction (BDR), Institut National de la Recherche Agronomique (INRA), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Centre National de la Recherche Scientifique (CNRS)-École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and Magdinier, Frederique

Subjects
CCCTC-Binding Factor, [SDV]Life Sciences [q-bio], Uterine Cervical Neoplasms, Plasma protein binding, Genome, 0302 clinical medicine, Genetics, 0303 health sciences, telomere, General Neuroscience, Subtelomere, Lamin Type A, Female, Insulator Elements, Cell Nucleolus, Protein Binding, congenital, hereditary, and neonatal diseases and abnormalities, Down-Regulation, HUMAIN, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Cell Line, Tumor, Animals, Humans, BIOLOGIE DU DEVELOPPEMENT, [INFO]Computer Science [cs], Molecular Biology, Locus control region, 030304 developmental biology, FSHD, D4Z4, General Immunology and Microbiology, Base Sequence, Carcinoma, genome stability & dynamics, Biological Transport, Epithelial Cells, Locus Control Region, CTCF, Telomere, Repressor Proteins, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Human genome, nuclear periphery, 030217 neurology & neurosurgery, Lamin
Abstract

International audience; The localization of genes within the nuclear space is of paramount importance for proper genome functions. However, very little is known on the cis-acting elements determining subnuclear positioning of chromosome segments. We show here that the D4Z4 human subtelomeric repeat localizes a telomere at the nuclear periphery. This perinuclear activity lies within an 80 bp sequence included within a region known to interact with CTCF and A-type Lamins. We further show that a reduced level of either CTCF or A-type Lamins suppresses the perinuclear activities of D4Z4 and that an array of multimerized D4Z4 sequence, which has lost its ability to bind CTCF and A-type Lamins, is not localized at the periphery. Overall, these findings reveal the existence of an 80 bp D4Z4 sequence that is sufficient to position an adjacent telomere to the nuclear periphery in a CTCF and A-type lamins-dependent manner. Strikingly, this sequence includes a 30 bp GA-rich motif, which binds CTCF and is present at several locations in the human genome.

Published
2009
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