A lipodystrophy-causing lamin A mutant alters conformation and epigenetic regulation of the anti-adipogenic MIR335 locus

• Published in: The Journal of cell biology Vol. 216; no. 9; pp. 2731 - 2743
• Main Authors: Oldenburg, Anja, Briand, Nolwenn, Sørensen, Anita L, Cahyani, Inswasti, Shah, Akshay, Moskaug, Jan Øivind, Collas, Philippe
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.09.2017; The Rockefeller University Press
• Subjects: Acetylation; Adipocytes - metabolism; Adipocytes - pathology; Adipogenesis - genetics; Body fat; Cell fate; Cells; Cells (biology); Cells, Cultured; Chromatin; Chromatin - genetics; Chromatin - metabolism; Chromatin Assembly and Disassembly; Clustering; Conformation; Deregulation; Differentiation; Enhancers; Epigenesis, Genetic; Epigenetics; Fibroblasts - metabolism; Fibroblasts - pathology; Gene expression; Genes; Genetic Predisposition to Disease; Histones - metabolism; Humans; Lamin Type A - genetics; Lamin Type A - metabolism; Lipodystrophy; Lipodystrophy, Familial Partial - genetics; Lipodystrophy, Familial Partial - metabolism; Lipodystrophy, Familial Partial - pathology; Lipodystrophy, Familial Partial - physiopathology; Metabolic disorders; Methylation; MicroRNAs - chemistry; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Mutation; Mutation hot spots; Nucleic Acid Conformation; Phenotype; Progenitor cells; Promoter Regions, Genetic; Ribonucleic acid; RNA; Stem cells; Stem Cells - metabolism; Stem Cells - pathology; Structure-Activity Relationship; Up-Regulation
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201701043

Mutations in the ( ) gene-encoding nuclear LMNA cause laminopathies, which include partial lipodystrophies associated with metabolic syndromes. The lipodystrophy-associated LMNA p.R482W mutation is known to impair adipogenic differentiation, but the mechanisms involved are unclear. We show in this study that the lamin A p.R482W hot spot mutation prevents adipogenic gene expression by epigenetically deregulating long-range enhancers of the anti-adipogenic microRNA gene in human adipocyte progenitor cells. The R482W mutation results in a loss of function of differentiation-dependent lamin A binding to the locus. This impairs H3K27 methylation and instead favors H3K27 acetylation on enhancers. The lamin A mutation further promotes spatial clustering of enhancer and promoter elements along with overexpression of the gene after adipogenic induction. Our results link a laminopathy-causing lamin A mutation to an unsuspected deregulation of chromatin states and spatial conformation of an miRNA locus critical for adipose progenitor cell fate.