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Systematic characterization of BAF mutations provides insights into intracomplex synthetic lethalities in human

Sandra Schick1,2, André F Rendeiro1, Kathrin Runggatscher1

  • 1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Nature Genetics
|August 21, 2019
PubMed

Insights

Loss-of-function mutations in BRG1/BRM associated factor (BAF) chromatin remodeling complexes drive cancer. This study reveals subunit-specific effects on BAF complex function, offering new therapeutic targets for BAF-mutant cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Aberrations in BRG1/BRM associated factor (BAF) chromatin remodeling complexes are common in human cancers.
  • The precise mechanisms by which these loss-of-function mutations contribute to tumorigenesis and potential therapeutic strategies remain unclear.
  • Cancer-type-specific mutation patterns suggest distinct roles for individual BAF subunits, potentially leading to aberrant complex formation.

Purpose of the Study:

  • To systematically investigate the impact of individual BAF subunit loss on BAF complex composition, chromatin accessibility, and gene expression.
  • To elucidate the functional consequences of specific subunit deficiencies in cancer development.
  • To identify potential therapeutic vulnerabilities in BAF-mutant cancers.

Main Methods:

  • Generation and analysis of a panel of knockout cell lines deficient for 22 different BAF subunits.
  • Comprehensive characterization of BAF complex composition, chromatin accessibility, and gene expression profiles.
  • Identification and analysis of intracomplex codependencies and synthetic lethal interactions.

Main Results:

  • Individual BAF subunit loss induces specific and significant alterations in complex composition, chromatin accessibility, and gene expression.
  • Observed alterations are subunit-dependent and explain known intracomplex codependencies, such as SMARCA4-ARID2, SMARCA4-ACTB, and SMARCC1-SMARCC2 synthetic lethality.
  • Demonstrated subunit-specific effects on BAF complex function and genome-wide chromatin organization.

Conclusions:

  • Loss of individual BAF subunits has distinct functional consequences, impacting chromatin organization and gene expression in specific ways.
  • Understanding these subunit-specific effects provides critical insights into BAF complex roles in cancer.
  • The identified functional alterations and synthetic lethal interactions offer promising avenues for the therapeutic targeting of BAF-mutant cancers.

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