Loss of BAF (mSWI/SNF) Complexes Causes Global Transcriptional and Chromatin State Changes in Forebrain Development

Cell Rep. 2015 Dec 1;13(9):1842-54. doi: 10.1016/j.celrep.2015.10.046. Epub 2015 Nov 19.

Abstract

BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knockout (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and downregulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3 and UTX) and potentiate their activity. Importantly, BAF complexes are indispensable for forebrain development, including proliferation, differentiation, and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls the global transcriptional program and chromatin state in development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cerebellar Cortex / metabolism
  • Chromatin / metabolism*
  • Chromosomal Proteins, Non-Histone / deficiency
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • DNA Helicases / metabolism
  • Down-Regulation
  • Embryo, Mammalian / metabolism
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism
  • Histones / genetics
  • Histones / metabolism
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Nuclear Proteins / metabolism
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Histones
  • Nuclear Proteins
  • Smarcc1 protein, mouse
  • Smarcc2 protein, mouse
  • Transcription Factors
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • Utx protein, mouse
  • Kdm6b protein, mouse
  • Smarca4 protein, mouse
  • DNA Helicases

Associated data

  • GEO/GSE73855