Brg1 Modulates Enhancer Activation in Mesoderm Lineage Commitment

Development. 2015 Apr 15;142(8):1418-30. doi: 10.1242/dev.109496. Epub 2015 Mar 26.

Abstract

The interplay between different levels of gene regulation in modulating developmental transcriptional programs, such as histone modifications and chromatin remodeling, is not well understood. Here, we show that the chromatin remodeling factor Brg1 is required for enhancer activation in mesoderm induction. In an embryonic stem cell-based directed differentiation assay, the absence of Brg1 results in a failure of cardiomyocyte differentiation and broad deregulation of lineage-specific gene expression during mesoderm induction. We find that Brg1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at distal enhancers that are activated during mesoderm induction. Brg1 is also required to maintain Polycomb-mediated repression of non-mesodermal developmental regulators, suggesting cooperativity between Brg1 and Polycomb complexes. Thus, Brg1 is essential for modulating active and repressive chromatin states during mesoderm lineage commitment, in particular the activation of developmentally important enhancers. These findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions.

Keywords: Chromatin; Enhancers; Gene expression; Histone modification; Mesoderm; Stem cells.

Publication types

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

MeSH terms

  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Lineage
  • Chromatin / metabolism
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism
  • Enhancer Elements, Genetic / genetics
  • Enhancer Elements, Genetic / physiology*
  • Gene Silencing / physiology
  • Histones / metabolism
  • Humans
  • Mesoderm / cytology
  • Mesoderm / metabolism
  • Mutation
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Polycomb-Group Proteins / metabolism
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / pharmacology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Chromatin
  • Histones
  • Nuclear Proteins
  • Polycomb-Group Proteins
  • Transcription Factors
  • Tamoxifen
  • afimoxifene
  • SMARCA4 protein, human
  • DNA Helicases

Associated data

  • GEO/GSE45448