Laminopathies disrupt epigenomic developmental programs and cell fate.
The nuclear envelope protein lamin A is encoded by thelamin A/C(LMNA) gene, which can contain missense mutations that cause Emery-Dreifuss muscular dystrophy (EDMD) (p.R453W). We fused mutated forms of the lamin A protein to bacterial DNA adenine methyltransferase (Dam) to define euchromatic-heterochromatin (epigenomic) transitions at the nuclear envelope during myogenesis (using DamID-seq). Lamin A missense mutations disrupted appropriate formation of lamin A-associated heterochromatin domains in an allele-specific manner-findings that were confirmed by chromatin immunoprecipitation-DNA sequencing (ChIP-seq) in murine H2K cells and DNA methylation studies in fibroblasts from muscular dystrophy patient who carried a distinctLMNAmutation (p.H222P). Observed perturbations of the epigenomic transitions included exit from pluripotency and cell cycle programs [euchromatin (open, transcribed) to heterochromatin (closed, silent)], as well as induction of myogenic loci (heterochromatin to euchromatin). In muscle biopsies from patients with either a gain- or change-of-functionLMNAgene mutation or a loss-of-function mutation in theemeringene, both of which cause EDMD, we observed inappropriate loss of heterochromatin formation at theSox2pluripotency locus, which was associated with persistent mRNA expression ofSox2 Overexpression ofSox2inhibited myogenic differentiation in human immortalized myoblasts. Our findings suggest that nuclear envelopathies are disorders of developmental epigenetic programming that result from altered formation of lamina-associated domains.
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA. Department of Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA.
Jelena
J
Perovanovic
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20852, USA.
Stefania
S
Dell'Orso
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
Viola F
VF
Gnochi
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA. Department of Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA.
Jyoti K
JK
Jaiswal
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20852, USA.
Vittorio
V
Sartorelli
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Laboratoire Commun de Biologie et Génétique Moléculaires, F-75012 Paris, France. INSERM UMR_S938, Centre de Recherche Saint-Antoine, F-75012 Paris, France. Sorbonne Universités, UPMC (Université Pierre et Marie Curie) Univ Paris 06, UMR_S938, F-75005 Paris, France. ICAN (Institute of Cardiometabolism and Nutrition), F-75013 Paris, France.
Corinne
C
Vigouroux
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, F-75013 Paris, France.
Kamel
K
Mamchaoui
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, F-75013 Paris, France.
Vincent
V
Mouly
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, F-75013 Paris, France.
Gisèle
G
Bonne
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA. Department of Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20010, USA. ehoffman@binghamton.edu.
Eric P
EP
Hoffman
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000235:genetics / Q000378:metabolism
D034904:Lamin Type A; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C058693:Dam methyltransferase; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)