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Valencia, Alfredo

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Valencia

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Alfredo

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Valencia, Alfredo

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Author's Publications: search.filters.isAuthorOfPublication.3e9f2866-c647-459f-b8c1-c180193f7444

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    SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters
    (2018) Nakayama, Robert T.; Pulice, John; Valencia, Alfredo; McBride, Matthew; McKenzie, Zachary; Gillespie, Mark A.; Ku, Wai Lim; Teng, Mingxiang; Cui, Kairong; Williams, Robert T.; Cassel, Seth; Qing, He; Widmer, Christian J.; Demetri, George; Irizarry, Rafael A.; Zhao, Keji; JeffRanish; Kadoch, Cigall
    Perturbations to mammalian SWI/SNF (BAF) complexes contribute to over 20% of human cancers, with driving roles first identified in malignant rhabdoid tumor (MRT), 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 intra-complex 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 BAF and PBAF complexes at enhancers and promoters, respectively, suggesting distinct functions of each complex which are perturbed upon BAF47 loss. Our results demonstrate collaborative mechanisms of mSWI/SNF-mediated gene activation, identifying functions that are coopted or abated to drive human cancers and developmental disorders.