Mutations in nuclear envelope change myogenic epigenomic programs and normal cell fate. J. Perovanovic1,2, S. Dell"orso3, V. Sartorelli3, K. Mamchaoui4,5, V. Mouly4,5, C. Vigouroux6,8,9,10, G. Bonne4,5,7, E. P. Hoffman1,2 1) Center for Genetic Medicine Research Children's National Medical Center, Washington, DC, 20010, USA; 2) Department of Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20010, USA; 3) Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20852, USA; 4) INSERM U974, F-75013, Paris, France; 5) Sorbonne Universités, UPMC Univ Paris 06, Myology Center of Research, UMRS974; Institut de Myologie, F-75013, Paris, France; 6) Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Tenon, Service de Biochimie et Hormonologie, F-75020, Paris, France; 7) Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, U.F. Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Paris F-75013, France; 8) INSERM UMR_S938, Centre de Recherche Saint-Antoine, F-75012, Paris, France; 9) Sorbonne Universités, UPMC Univ Paris 06, UMR_S938, F-75005, Paris, France; 10) ICAN, Institute of Cardiometabolism and Nutrition, Paris, France.
Mutations of LMNA cause wide spectrum disorders and exhibit allelic heterogeneity of post mitotic tissue with mutation specific phenotypes. One of the phenotypes is Emery-Dreifuss Muscular Dystrophy (EDMD (MIM 300200 and MIM 181350) where LMNA mutations and loss-of-function mutations in EMD specifically affect muscle tissue. Here we show that EMD and LMNA mutations alter epigenomic programming during myogenesis via shared locus-specific perturbations of chromatin-nuclear envelope interactions. ChIP-seq (H3K9me3) showed that loss of emerin from myogenic cells leads to decrease in heterochromatin enrichment on key cell fate regulators and re-activation of signaling pathways involved in stem cell differentiation. Specifically, ChIP-seq show differential silencing of the Sox2 locus and its downstream targets in emerin null cells, suggesting that commitment to myogenic lineages was perturbed. To determine if EDMD-AD (MIM 181350) LMNA mutations showed allele-specific perturbations of myogenic SOX2 silencing and downstream targets, patient-derived normal, EDMD-AD (MIM 181350) (p.H222P), and Familial Partial Lipodystrophy (FPLD (MIM 151660)) (p.R482W) cells were studied by ChIP and qRT-PCR. Analysis showed allele-specific epigenomic perturbation of myogenic silencing at the SOX2 locus. Furthermore, EDMD patient muscle biopsies showed disease-specific overexpression of SOX2 pathways relative to normal and disease-control (FKRP (MIM 607155)) muscles. Direct interaction between wild-type LMNA protein and the SOX2 locus was shown by DamID methods, and these interactions were disrupted by LMNA disease mutations. These findings suggest that nuclear envelope disorders cause allele-specific alterations in cell commitment via inadequate epigenomic programming.
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