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Wang, Xiaofeng

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Wang

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Xiaofeng

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Wang, Xiaofeng

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2014 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.e299a479-d7ee-4ab3-8404-e3845639a674

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Now showing 1 - 3 of 3
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    The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers
    (Nature Publishing Group, 2017) Alver, Burak; Kim, Kimberly H.; Lu, Ping; Wang, Xiaofeng; Manchester, Haley; Wang, Weishan; Haswell, Jeffrey; Park, Peter; Roberts, Charles W. M.
    Genes encoding subunits of SWI/SNF (BAF) chromatin remodelling complexes are collectively altered in over 20% of human malignancies, but the mechanisms by which these complexes alter chromatin to modulate transcription and cell fate are poorly understood. Utilizing mouse embryonic fibroblast and cancer cell line models, here we show via ChIP-seq and biochemical assays that SWI/SNF complexes are preferentially targeted to distal lineage specific enhancers and interact with p300 to modulate histone H3 lysine 27 acetylation. We identify a greater requirement for SWI/SNF at typical enhancers than at most super-enhancers and at enhancers in untranscribed regions than in transcribed regions. Our data further demonstrate that SWI/SNF-dependent distal enhancers are essential for controlling expression of genes linked to developmental processes. Our findings thus establish SWI/SNF complexes as regulators of the enhancer landscape and provide insight into the roles of SWI/SNF in cellular fate control.
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    ARID1B is a specific vulnerability in ARID1A-mutant cancers
    (2014) Helming, Katherine C.; Wang, Xiaofeng; Wilson, Boris G.; Vazquez, Francisca; Haswell, Jeffrey; Manchester, Haley; Kim, Youngha; Kryukov, Gregory V.; Ghandi, Mahmoud; Aguirre, Andrew; Jagani, Zainab; Wang, Zhong; Garraway, Levi A.; Hahn, William C.; Roberts, Charles W. M.
    Summary Recent studies have revealed that ARID1A is frequently mutated across a wide variety of human cancers and also has bona fide tumor suppressor properties. Consequently, identification of vulnerabilities conferred by ARID1A mutation would have major relevance for human cancer. Here, using a broad screening approach, we identify ARID1B, a related but mutually exclusive homolog of ARID1A in the SWI/SNF chromatin remodeling complex, as the number one gene preferentially required for the survival of ARID1A-mutant cancer cell lines. We show that loss of ARID1B in ARID1A-deficient backgrounds destabilizes SWI/SNF and impairs proliferation. Intriguingly, we also find that ARID1A and ARID1B are frequently co-mutated in cancer, but that ARID1A-deficient cancers retain at least one ARID1B allele. These results suggest that loss of ARID1A and ARID1B alleles cooperatively promotes cancer formation but also results in a unique functional dependence. The results further identify ARID1B as a potential therapeutic target for ARID1A-mutant cancers.
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    SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation
    (2016) Wang, Xiaofeng; Lee, Ryan; Alver, Burak; Haswell, Jeffrey; Wang, Su; Mieczkowski, Jakub; Drier, Yotam; Gillespie, Shawn M.; Archer, Tenley; Wu, Jennifer; Tzvetkov, Evgeni P.; Troisi, Emma C.; Pomeroy, Scott; Biegel, Jaclyn A.; Tolstorukov, Michael; Bernstein, Bradley; Park, Peter; Roberts, Charles W. M.
    SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex1,2, is inactivated in nearly all pediatric rhabdoid tumors3–5. These aggressive cancers are among the most genomically stable6–8, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human rhabdoid tumors show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting – markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers, like SOX2 in brain-derived rhabdoid tumors. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.