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Alver, Burak

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Alver, Burak

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2014 - 20176

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Author's Publications: search.filters.isAuthorOfPublication.5f12bd4d-8006-47f8-82b7-8aacdc7164ed

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Now showing 1 - 6 of 6
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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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    Nucleosomal occupancy changes locally over key regulatory regions during cell differentiation and reprogramming
    (2014) West, Jason A.; Cook, April; Alver, Burak; Stadtfeld, Matthias; Deaton, Aimee; Hochedlinger, Konrad; Park, Peter; Tolstorukov, Michael Y.; Kingston, Robert
    Chromatin structure determines DNA accessibility. We compare nucleosome occupancy in mouse and human embryonic stem cells (ESCs), induced-pluripotent stem cells (iPSCs), and differentiated cell types using MNase-seq. To address variability inherent in this technique, we developed a bioinformatic approach to identify regions of difference (RoD) in nucleosome occupancy between pluripotent and somatic cells. Surprisingly, most chromatin remains unchanged; a majority of rearrangements appear to affect a single nucleosome. RoDs are enriched at genes and regulatory elements, including enhancers associated with pluripotency and differentiation. RoDs co-localize with binding sites of key developmental regulators, including the reprogramming factors Klf4, Oct4/Sox2, and c-Myc. Nucleosomal landscapes in ESC enhancers are extensively altered, exhibiting lower nucleosome occupancy in pluripotent cells than in somatic cells. Most changes are reset during reprogramming. We conclude that changes in nucleosome occupancy are a hallmark of cell differentiation and reprogramming and likely identify regulatory regions essential for these processes.
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    Comparative Analysis of the Transcriptome across Distant Species
    (2014) Gerstein, Mark B.; Rozowsky, Joel; Yan, Koon-Kiu; Wang, Daifeng; Cheng, Chao; Brown, James B.; Davis, Carrie A; Hillier, LaDeana; Sisu, Cristina; Li, Jingyi Jessica; Pei, Baikang; Harmanci, Arif O.; Duff, Michael O.; Djebali, Sarah; Alexander, Roger P.; Alver, Burak; Auerbach, Raymond; Bell, Kimberly; Bickel, Peter J.; Boeck, Max E.; Boley, Nathan P.; Booth, Benjamin W.; Cherbas, Lucy; Cherbas, Peter; Di, Chao; Dobin, Alex; Drenkow, Jorg; Ewing, Brent; Fang, Gang; Fastuca, Megan; Feingold, Elise A.; Frankish, Adam; Gao, Guanjun; Good, Peter J.; Guigó, Roderic; Hammonds, Ann; Harrow, Jen; Hoskins, Roger A.; Howald, Cédric; Hu, Long; Huang, Haiyan; Hubbard, Tim J. P.; Huynh, Chau; Jha, Sonali; Kasper, Dionna; Kato, Masaomi; Kaufman, Thomas C.; Kitchen, Robert R.; Ladewig, Erik; Lagarde, Julien; Lai, Eric; Leng, Jing; Lu, Zhi; MacCoss, Michael; May, Gemma; McWhirter, Rebecca; Merrihew, Gennifer; Miller, David M.; Mortazavi, Ali; Murad, Rabi; Oliver, Brian; Olson, Sara; Park, Peter; Pazin, Michael J.; Perrimon, Norbert; Pervouchine, Dmitri; Reinke, Valerie; Reymond, Alexandre; Robinson, Garrett; Samsonova, Anastasia; Saunders, Gary I.; Schlesinger, Felix; Sethi, Anurag; Slack, Frank J.; Spencer, William C.; Stoiber, Marcus H.; Strasbourger, Pnina; Tanzer, Andrea; Thompson, Owen A.; Wan, Kenneth H.; Wang, Guilin; Wang, Huaien; Watkins, Kathie L.; Wen, Jiayu; Wen, Kejia; Xue, Chenghai; Yang, Li; Yip, Kevin; Zaleski, Chris; Zhang, Yan; Zheng, Henry; Brenner, Steven E.; Graveley, Brenton R.; Celniker, Susan E.; Gingeras, Thomas R; Waterston, Robert
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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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    MNase titration reveals differences between nucleosome occupancy and chromatin accessibility
    (Nature Publishing Group, 2016) Mieczkowski, Jakub; Cook, April; Bowman, Sarah K.; Mueller, Britta; Alver, Burak; Kundu, Sharmistha; Deaton, Aimee M.; Urban, Jennifer A.; Larschan, Erica; Park, Peter; Kingston, Robert; Tolstorukov, Michael Y.
    Chromatin accessibility plays a fundamental role in gene regulation. Nucleosome placement, usually measured by quantifying protection of DNA from enzymatic digestion, can regulate accessibility. We introduce a metric that uses micrococcal nuclease (MNase) digestion in a novel manner to measure chromatin accessibility by combining information from several digests of increasing depths. This metric, MACC (MNase accessibility), quantifies the inherent heterogeneity of nucleosome accessibility in which some nucleosomes are seen preferentially at high MNase and some at low MNase. MACC interrogates each genomic locus, measuring both nucleosome location and accessibility in the same assay. MACC can be performed either with or without a histone immunoprecipitation step, and thereby compares histone and non-histone protection. We find that changes in accessibility at enhancers, promoters and other regulatory regions do not correlate with changes in nucleosome occupancy. Moreover, high nucleosome occupancy does not necessarily preclude high accessibility, which reveals novel principles of chromatin regulation.
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    Comparative Analysis of the Transcriptome Across Distant Species
    (Springer Science and Business Media LLC, 2014-08-27) Gerstein, Mark B.; Rozowsky, Joel; Yan, Koon-Kiu; Wang, Daifeng; Cheng, Chao; Brown, James B.; Davis, Carrie A.; Hillier, LaDeana; Sisu, Cristina; Li, Jingyi Jessica; Pei, Baikang; Harmanci, Arif O.; Duff, Michael O.; Djebali, Sarah; Alexander, Roger P.; Alver, Burak; Auerbach, Raymond; Bell, Kimberly; Bickel, Peter J.; Boeck, Max E.; Boley, Nathan P.; Booth, Benjamin W.; Cherbas, Lucy; Cherbas, Peter; Di, Chao; Dobin, Alex; Drenkow, Jorg; Ewing, Brent; Fang, Gang; Fastuca, Megan; Feingold, Elise A.; Frankish, Adam; Gao, Guanjun; Good, Peter J.; Guigó, Roderic; Hammonds, Ann; Harrow, Jen; Hoskins, Roger A.; Howald, Cédric; Hu, Long; Huang, Haiyan; Hubbard, Tim J. P.; Huynh, Chau; Jha, Sonali; Kasper, Dionna; Kato, Masaomi; Kaufman, Thomas C.; Kitchen, Robert R.; Ladewig, Erik; Lagarde, Julien; Lai, Eric; Leng, Jing; Lu, Zhi; MacCoss, Michael; May, Gemma; McWhirter, Rebecca; Merrihew, Gennifer; Miller, David M.; Mortazavi, Ali; Murad, Rabi; Oliver, Brian; Olson, Sara; Park, Peter; Pazin, Michael J.; Perrimon, Norbert; Pervouchine, Dmitri; Reinke, Valerie; Reymond, Alexandre; Robinson, Garrett; Samsonova, Anastasia; Saunders, Gary I.; Schlesinger, Felix; Sethi, Anurag; Slack, Frank J.; Spencer, William C.; Stoiber, Marcus H.; Strasbourger, Pnina; Tanzer, Andrea; Thompson, Owen A.; Wan, Kenneth H.; Wang, Guilin; Wang, Huaien; Watkins, Kathie L.; Wen, Jiayu; Wen, Kejia; Xue, Chenghai; Yang, Li; Yip, Kevin; Zaleski, Chris; Zhang, Yan; Zheng, Henry; Brenner, Steven E.; Graveley, Brenton R.; Celniker, Susan E.; Gingeras, Thomas R.; Waterston, Robert
    The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features1,2,3,4,5,6. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a ‘universal model’ based on a single set of organism-independent parameters.