RRC ID 63749
著者 Nakayama RT, Pulice JL, Valencia AM, McBride MJ, McKenzie ZM, Gillespie MA, Ku WL, Teng M, Cui K, Williams RT, Cassel SH, Qing H, Widmer CJ, Demetri GD, Irizarry RA, Zhao K, Ranish JA, Kadoch C.
タイトル SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters.
ジャーナル Nat Genet
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.
巻・号 49(11)
ページ 1613-1623
公開日 2017-11-1
DOI 10.1038/ng.3958
PII ng.3958
PMID 28945250
PMC PMC5803080
MeSH 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
IF 27.605
リソース情報
ヒト・動物細胞 HS-ES-1(RCB2364) HS-ES-2R(RCB2361) HS-ES-2M(RCB2360)