Phosphorylated Lamin A/C in the Nuclear Interior Binds Active Enhancers Associated with Abnormal Transcription in Progeria

Dev Cell. 2020 Mar 23;52(6):699-713.e11. doi: 10.1016/j.devcel.2020.02.011.


LMNA encodes nuclear Lamin A/C that tethers lamina-associated domains (LADs) to the nuclear periphery. Mutations in LMNA cause degenerative disorders including the premature aging disorder Hutchinson-Gilford progeria, but the mechanisms are unknown. We report that Ser22-phosphorylated (pS22) Lamin A/C was localized to the nuclear interior in human fibroblasts throughout the cell cycle. pS22-Lamin A/C interacted with a subset of putative active enhancers, not LADs, at locations co-bound by the transcriptional activator c-Jun. In progeria-patient fibroblasts, a subset of pS22-Lamin A/C-binding sites were lost, whereas new pS22-Lamin A/C-binding sites emerged in normally quiescent loci. New pS22-Lamin A/C binding was accompanied by increased histone acetylation, increased c-Jun binding, and upregulation of nearby genes implicated in progeria pathophysiology. These results suggest that Lamin A/C regulates gene expression by enhancer binding. Disruption of the gene regulatory rather than LAD tethering function of Lamin A/C may underlie the pathogenesis of disorders caused by LMNA mutations.

Keywords: Hutchinson-Gilford progeria; LMNA; Lamin A/C; c-Jun; enhancer; lamina-associated domain (LAD); laminopathies; nuclear lamina; phosphorylation; transcription.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Adolescent
  • Binding Sites
  • Cell Line
  • Cell Nucleus / metabolism*
  • Cells, Cultured
  • Child
  • Enhancer Elements, Genetic*
  • Fibroblasts / metabolism
  • Humans
  • Lamin Type A / chemistry
  • Lamin Type A / genetics*
  • Lamin Type A / metabolism
  • Male
  • Mutation*
  • Progeria / genetics*
  • Protein Binding


  • LMNA protein, human
  • Lamin Type A