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SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters.
- Source :
-
Nature genetics [Nat Genet] 2017 Nov; Vol. 49 (11), pp. 1613-1623. Date of Electronic Publication: 2017 Sep 25. - Publication Year :
- 2017
-
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.
- Subjects :
- Carcinogenesis metabolism
Carcinogenesis pathology
Cell Line, Tumor
Chromatin chemistry
Chromatin metabolism
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone metabolism
Enhancer Elements, Genetic
Genetic Complementation Test
Humans
Polycomb-Group Proteins genetics
Polycomb-Group Proteins metabolism
Promoter Regions, Genetic
Rhabdoid Tumor metabolism
Rhabdoid Tumor pathology
SMARCB1 Protein deficiency
Sarcoma metabolism
Sarcoma pathology
Transcription Factors metabolism
Carcinogenesis genetics
Chromosomal Proteins, Non-Histone genetics
Gene Expression Regulation, Neoplastic
Rhabdoid Tumor genetics
SMARCB1 Protein genetics
Sarcoma genetics
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 49
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 28945250
- Full Text :
- https://doi.org/10.1038/ng.3958