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

J Cell Biol. 2017 Sep 4;216(9):2731-2743. doi: 10.1083/jcb.201701043. Epub 2017 Jul 27.


Mutations in the Lamin A/C (LMNA) 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 MIR335 microRNA gene in human adipocyte progenitor cells. The R482W mutation results in a loss of function of differentiation-dependent lamin A binding to the MIR335 locus. This impairs H3K27 methylation and instead favors H3K27 acetylation on MIR335 enhancers. The lamin A mutation further promotes spatial clustering of MIR335 enhancer and promoter elements along with overexpression of the MIR355 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adipocytes* / metabolism
  • Adipocytes* / pathology
  • Adipogenesis / genetics*
  • Cells, Cultured
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly
  • Epigenesis, Genetic*
  • Fibroblasts* / metabolism
  • Fibroblasts* / pathology
  • Genetic Predisposition to Disease
  • Histones / metabolism
  • Humans
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism
  • Lipodystrophy, Familial Partial / genetics*
  • Lipodystrophy, Familial Partial / metabolism
  • Lipodystrophy, Familial Partial / pathology
  • Lipodystrophy, Familial Partial / physiopathology
  • Methylation
  • MicroRNAs / chemistry
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Mutation*
  • Nucleic Acid Conformation
  • Phenotype
  • Promoter Regions, Genetic
  • Stem Cells* / metabolism
  • Stem Cells* / pathology
  • Structure-Activity Relationship
  • Up-Regulation


  • Chromatin
  • Histones
  • LMNA protein, human
  • Lamin Type A
  • MIRN335 microRNA, human
  • MicroRNAs

Associated data

  • PIR/151660