Dominant-negative SMARCA4 mutants alter the accessibility landscape of tissue-unrestricted enhancers

Nat Struct Mol Biol. 2018 Jan;25(1):61-72. doi: 10.1038/s41594-017-0007-3. Epub 2017 Dec 11.


Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1. Affected positions include hundreds of sites identified as superenhancers in many tissues. Dominant-negative mutation induces pro-oncogenic expression changes, including increased expression of Myc and its target genes. Together, our data suggest that disruption of enhancer accessibility represents a key source of altered function in disorders with SMARCA4 mutations in a wide variety of tissues.

Publication types

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

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Animals
  • Chromatin / chemistry
  • Chromatin Assembly and Disassembly
  • Culture Media
  • DNA Helicases / genetics*
  • Enhancer Elements, Genetic
  • Epigenomics
  • Genes, Dominant*
  • Genotype
  • Heterozygote
  • Humans
  • Mice
  • Mice, Transgenic
  • Mouse Embryonic Stem Cells / cytology
  • Multivariate Analysis
  • Mutation*
  • Mutation, Missense
  • Neoplasms / genetics
  • Nuclear Proteins / genetics*
  • Polycomb-Group Proteins / genetics
  • Sequence Analysis, RNA
  • Transcription Factors / genetics*


  • Chromatin
  • Culture Media
  • Nuclear Proteins
  • Polycomb-Group Proteins
  • Transcription Factors
  • Adenosine Triphosphatases
  • SMARCA4 protein, human
  • DNA Helicases