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Lee, Ryan

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Lee, Ryan

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2015 - 20162

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Author's Publications: search.filters.isAuthorOfPublication.dda95c89-bf44-4bed-bbb1-a42081a9d7d3

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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.
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    Mechanisms of Oncogenesis Driven by SNF5-Loss in Pediatric Rhabdoid Tumors
    (2015-05-16) Lee, Ryan; Polyak, Kornelia; Roberts, Charles; Meyerson, Matthew; Bernstein, Bradley
    The characterization of inactivating mutations affecting SNF5 in pediatric rhabdoid tumors constituted the first clear connection between an epigenetic regulator and tumor formation. SNF5 is a core subunit of the evolutionarily conserved SWI/SNF chromatin remodeling complex, a complex that has recently emerged as being frequently mutated across a wide spectrum of cancers. However, the exact mechanism by which SNF5 loss causes rhabdoid tumor, and SWI/SNF mutations are involved cancers generally, remains undetermined. Since SWI/SNF is a chromatin remodeling complex, it is unclear whether the perturbation of chromatin structure and epigenetic dysregulation caused by SNF5 loss alone may drive cancer formation or if SNF5 mutations are dependent on additional cooperative somatic mutations. In order to determine what, if any, additional pathways cooperate with SNF5 loss, we have sequenced the exomes of 35 primary rhabdoid tumors. Despite the lethal nature of these cancers, we identified remarkably few coding mutations, with SNF5 loss being the only significantly recurring event. The mutation rate of rhabdoid tumors is among the lowest of all cancer genomes sequenced to date. Our results demonstrate that loss of SNF5 alone appears to a genetic event sufficient to drive rhabdoid tumor and that genomic instability and high mutation rates are not required for oncogenesis. Because SNF5 loss is the only known genetic driver of these cancers, RT represents a good model system in which to study the effects of SWI/SNF subunit mutations on driving oncogenesis through disruption of transcriptional regulation. As one means of evaluating such disruptions, we performed chromatin immunoprecipitation-sequencing of histone modifications in primary RT tissues and RT cell lines. Despite being genetically indistinguishable, RT group according to tissue of origin when characterized by H3K27ac at active enhancers. Additionally, we found that SNF5 loss impairs SWI/SNF binding to enhancers, but its loss has minimal effect on the targeting of SWI/SNF to super-enhancers. Our data suggest a model whereby SNF5 loss blocks acquisition of enhancers required for differentiation but leaves intact super-enhancer structures that underlie the proliferative fate of the progenitor cells of origin. These studies collectively characterize an epigenetic mechanism underlying tumor formation upon SNF5 loss.