ACTL6a enforces the epidermal progenitor state by suppressing SWI/SNF-dependent induction of KLF4

Cell Stem Cell. 2013 Feb 7;12(2):193-203. doi: 10.1016/j.stem.2012.12.014.

Abstract

Somatic progenitors suppress differentiation to maintain tissue self-renewal. The mammalian SWI/SNF chromatin-remodeling complex regulates nucleosome packaging to control differentiation in embryonic and adult stem cells. Catalytic Brg1 and Brm subunits are required for these processes; however, the roles of SWI/SNF regulatory subunits are not fully understood. Here, we show that ACTL6a/BAF53A modulates the SWI/SNF complex to suppress differentiation in epidermis. Conditional loss of ACTL6a resulted in terminal differentiation, cell-cycle exit, and hypoplasia, whereas ectopic expression of ACTL6a promoted the progenitor state. A significant portion of genes regulated by ACTL6a were found to also be targets of KLF4, a known activator of epidermal differentiation. Mechanistically, we show that ACTL6a prevents SWI/SNF complex binding to promoters of KLF4 and other differentiation genes and that SWI/SNF catalytic subunits are required for full induction of KLF4 targets. Thus, ACTL6a controls the epidermal progenitor state by sequestering SWI/SNF to prevent activation of differentiation programs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / genetics
  • Actins / metabolism*
  • Animals
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • ACTL6A protein, human
  • Actins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • GKLF protein
  • Kruppel-Like Transcription Factors

Associated data

  • GEO/GSE36222