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

Robert T. Nakayama, John L. Pulice, Alfredo M. Valencia, Matthew J. McBride, Zachary M. McKenzie, Mark A. Gillespie, Wai Lim Ku, Mingxiang Teng, Kairong Cui, Robert T. Williams, Seth H. Cassel, He Qing, Christian J. Widmer, George D. Demetri, Rafael A. Irizarry, Keji Zhao, Jeffrey A. Ranish, Cigall Kadoch

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70 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1613-1623
Number of pages11
JournalNature genetics
Volume49
Issue number11
DOIs
Publication statusPublished - 2017 Nov 1

ASJC Scopus subject areas

  • Genetics

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    Nakayama, R. T., Pulice, J. L., Valencia, A. M., McBride, M. J., McKenzie, Z. M., Gillespie, M. A., Ku, W. L., Teng, M., Cui, K., Williams, R. T., Cassel, S. H., Qing, H., Widmer, C. J., Demetri, G. D., Irizarry, R. A., Zhao, K., Ranish, J. A., & Kadoch, C. (2017). SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters. Nature genetics, 49(11), 1613-1623. https://doi.org/10.1038/ng.3958