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dc.contributor.authorZhang, Xiaolan
dc.contributor.authorWang, Li
dc.contributor.authorMelnikov, Alexandre
dc.contributor.authorRogov, Peter
dc.contributor.authorTewhey, Ryan
dc.contributor.authorIsakova, Alina
dc.contributor.authorDeplancke, Bart
dc.contributor.authorBernstein, Bradley E.
dc.contributor.authorMikkelsen, Tarjei S.
dc.contributor.authorGrossman, Sharon Rachel
dc.contributor.authorEngreitz, Jesse Michael
dc.contributor.authorLander, Eric Steven
dc.date.accessioned2017-09-14T19:55:36Z
dc.date.available2017-09-14T19:55:36Z
dc.date.issued2017-01
dc.date.submitted2016-12
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/111218
dc.description.abstractEnhancers regulate gene expression through the binding of sequence-specific transcription factors (TFs) to cognate motifs. Various features influence TF binding and enhancer function—including the chromatin state of the genomic locus, the affinities of the binding site, the activity of the bound TFs, and interactions among TFs. However, the precise nature and relative contributions of these features remain unclear. Here, we used massively parallel reporter assays (MPRAs) involving 32,115 natural and synthetic enhancers, together with high-throughput in vivo binding assays, to systematically dissect the contribution of each of these features to the binding and activity of genomic regulatory elements that contain motifs for PPARγ, a TF that serves as a key regulator of adipogenesis. We show that distinct sets of features govern PPARγ binding vs. enhancer activity. PPARγ binding is largely governed by the affinity of the specific motif site and higher-order features of the larger genomic locus, such as chromatin accessibility. In contrast, the enhancer activity of PPARγ binding sites depends on varying contributions from dozens of TFs in the immediate vicinity, including interactions between combinations of these TFs. Different pairs of motifs follow different interaction rules, including subadditive, additive, and superadditive interactions among specific classes of TFs, with both spatially constrained and flexible grammars. Our results provide a paradigm for the systematic characterization of the genomic features underlying regulatory elements, applicable to the design of synthetic regulatory elements or the interpretation of human genetic variation.en_US
dc.description.sponsorshipNational Human Genome Research Institute (U.S.) (Grant 2U54HG003067-10)en_US
dc.description.sponsorshipNational Institute of General Medical Sciences (U.S.) (Grant T32GM007753)en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1621150114en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.titleSystematic dissection of genomic features determining transcription factor binding and enhancer functionen_US
dc.typeArticleen_US
dc.identifier.citationGrossman, Sharon R. et al. “Systematic Dissection of Genomic Features Determining Transcription Factor Binding and Enhancer Function.” Proceedings of the National Academy of Sciences 114, 7 (February 2017): E1291–E1300 © 2017 National Academy of Sciencesen_US
dc.contributor.departmentInstitute for Medical Engineering and Scienceen_US
dc.contributor.departmentBroad Institute of MIT and Harvarden_US
dc.contributor.departmentHarvard University--MIT Division of Health Sciences and Technologyen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorGrossman, Sharon Rachel
dc.contributor.mitauthorEngreitz, Jesse Michael
dc.contributor.mitauthorLander, Eric Steven
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsGrossman, Sharon R.; Zhang, Xiaolan; Wang, Li; Engreitz, Jesse; Melnikov, Alexandre; Rogov, Peter; Tewhey, Ryan; Isakova, Alina; Deplancke, Bart; Bernstein, Bradley E.; Mikkelsen, Tarjei S.; Lander, Eric S.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0001-5410-7274
dc.identifier.orcidhttps://orcid.org/0000-0002-5754-1719
mit.licensePUBLISHER_POLICYen_US


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