SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters

Nat Genet. 2017 Nov;49(11):1613-1623. doi: 10.1038/ng.3958. Epub 2017 Sep 25.

Abstract

Perturbations to mammalian SWI/SNF (mSWI/SNF or BAF) complexes contribute to more than 20% of human cancers, with driving roles first identified in malignant rhabdoid tumor, an aggressive pediatric cancer characterized by biallelic inactivation of the core BAF complex subunit SMARCB1 (BAF47). However, the mechanism by which this alteration contributes to tumorigenesis remains poorly understood. We find that BAF47 loss destabilizes BAF complexes on chromatin, absent significant changes in complex assembly or integrity. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in increased genome-wide BAF complex occupancy, facilitating widespread enhancer activation and opposition of Polycomb-mediated repression at bivalent promoters. We demonstrate differential regulation by two distinct mSWI/SNF assemblies, BAF and PBAF complexes, enhancers and promoters, respectively, suggesting that each complex has distinct functions that are perturbed upon BAF47 loss. Our results demonstrate collaborative mechanisms of mSWI/SNF-mediated gene activation, identifying functions that are co-opted or abated to drive human cancers and developmental disorders.

MeSH terms

  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Neoplastic*
  • Genetic Complementation Test
  • Humans
  • Polycomb-Group Proteins / genetics
  • Polycomb-Group Proteins / metabolism
  • Promoter Regions, Genetic
  • Rhabdoid Tumor / genetics*
  • Rhabdoid Tumor / metabolism
  • Rhabdoid Tumor / pathology
  • SMARCB1 Protein / deficiency
  • SMARCB1 Protein / genetics*
  • Sarcoma / genetics*
  • Sarcoma / metabolism
  • Sarcoma / pathology
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism

Substances

  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • Polycomb-Group Proteins
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • SWI-SNF-B chromatin-remodeling complex
  • Transcription Factors