BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors

Nat Commun. 2019 Apr 23;10(1):1881. doi: 10.1038/s41467-019-09891-7.

Abstract

Bromodomain-containing protein 9 (BRD9) is a recently identified subunit of SWI/SNF(BAF) chromatin remodeling complexes, yet its function is poorly understood. Here, using a genome-wide CRISPR-Cas9 screen, we show that BRD9 is a specific vulnerability in pediatric malignant rhabdoid tumors (RTs), which are driven by inactivation of the SMARCB1 subunit of SWI/SNF. We find that BRD9 exists in a unique SWI/SNF sub-complex that lacks SMARCB1, which has been considered a core subunit. While SMARCB1-containing SWI/SNF complexes are bound preferentially at enhancers, we show that BRD9-containing complexes exist at both promoters and enhancers. Mechanistically, we show that SMARCB1 loss causes increased BRD9 incorporation into SWI/SNF thus providing insight into BRD9 vulnerability in RTs. Underlying the dependency, while its bromodomain is dispensable, the DUF3512 domain of BRD9 is essential for SWI/SNF integrity in the absence of SMARCB1. Collectively, our results reveal a BRD9-containing SWI/SNF subcomplex is required for the survival of SMARCB1-mutant RTs.

Publication types

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

MeSH terms

  • CRISPR-Cas Systems / genetics
  • Cell Line, Tumor
  • Chromatin Assembly and Disassembly*
  • Enhancer Elements, Genetic / genetics
  • Gene Knockdown Techniques
  • Gene Knockout Techniques
  • Humans
  • Mutation
  • Promoter Regions, Genetic / genetics
  • Protein Domains / drug effects
  • RNA, Small Interfering / metabolism
  • Rhabdoid Tumor / genetics*
  • Rhabdoid Tumor / pathology
  • SMARCB1 Protein / genetics*
  • SMARCB1 Protein / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • BRD9 protein, human
  • RNA, Small Interfering
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors