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

H Courtney Hodges1, Benjamin Z Stanton2,3,4, Katerina Cermakova1,5

  • 1Department of Molecular & Cellular Biology, Center for Precision Environmental Health, and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.

Nature Structural & Molecular Biology
|January 12, 2018
PubMed

Insights

SMARCA4 (BRG1) mutations disrupt DNA accessibility and enhancer function, leading to cancer-promoting gene expression changes. These findings clarify the role of SMARCA4 missense mutations in various diseases.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Biology

Background:

  • SMARCA4 (BRG1) mutations are linked to cancers and neurological disorders.
  • The impact of SMARCA4 missense mutations on cellular function remains unclear.

Purpose of the Study:

  • To investigate the functional consequences of SMARCA4 cancer missense mutations.
  • To elucidate the molecular mechanisms by which these mutations contribute to disease.

Main Methods:

  • Analysis of SMARCA4 cancer missense mutations targeting ATPase surfaces.
  • Assessment of chromatin accessibility landscape alterations.
  • Evaluation of gene expression changes, including Myc and its targets.

Main Results:

  • SMARCA4 mutations disrupt the ATPase activity and mechanochemical cycle of BAF/PBAF complexes.
  • Heterozygous expression of mutants alters chromatin accessibility genome-wide, particularly at active enhancers.
  • Mutations lead to pro-oncogenic expression changes, including increased Myc activity.

Conclusions:

  • Disruption of enhancer accessibility by SMARCA4 mutations is a key pathogenic mechanism.
  • These findings provide insights into SMARCA4-associated malignancies and neurologic disorders.
  • Understanding these mechanisms can inform therapeutic strategies for SMARCA4-related diseases.

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