Srf destabilizes cellular identity by suppressing cell-type-specific gene expression programs

Nat Commun. 2018 Apr 11;9(1):1387. doi: 10.1038/s41467-018-03748-1.


Multicellular organisms consist of multiple cell types. The identity of these cells is primarily maintained by cell-type-specific gene expression programs; however, mechanisms that suppress these programs are poorly defined. Here we show that serum response factor (Srf), a transcription factor that is activated by various extracellular stimuli, can repress cell-type-specific genes and promote cellular reprogramming to pluripotency. Manipulations that decrease β-actin monomer quantity result in the nuclear accumulation of Mkl1 and the activation of Srf, which downregulate cell-type-specific genes and alter the epigenetics of regulatory regions and chromatin organization. Mice overexpressing Srf exhibit various pathologies including an ulcerative colitis-like symptom and a metaplasia-like phenotype in the pancreas. Our results demonstrate an unexpected function of Srf via a mechanism by which extracellular stimuli actively destabilize cell identity and suggest Srf involvement in a wide range of diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Cell Differentiation
  • Cellular Reprogramming / genetics
  • Chromatin / chemistry*
  • Chromatin / metabolism
  • Colitis, Ulcerative / genetics*
  • Colitis, Ulcerative / metabolism
  • Colitis, Ulcerative / pathology
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Male
  • Metaplasia / genetics*
  • Metaplasia / metabolism
  • Metaplasia / pathology
  • Mice
  • Mice, Transgenic
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Pancreas / metabolism*
  • Pancreas / pathology
  • Serum Response Factor / genetics*
  • Serum Response Factor / metabolism
  • Signal Transduction
  • Trans-Activators / genetics
  • Trans-Activators / metabolism


  • Actins
  • Chromatin
  • Mrtfa protein, mouse
  • Serum Response Factor
  • Trans-Activators