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Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis

dc.contributor.authorSuzuki, Hiroshi
dc.contributor.authorYoung, Richard A.
dc.contributor.authorSharp, Phillip A.
dc.date.accessioned2018-07-10T14:44:20Z
dc.date.available2018-07-10T14:44:20Z
dc.date.issued2017-03
dc.date.submitted2017-02
dc.identifier.issn0092-8674
dc.identifier.issn1097-4172
dc.identifier.urihttp://hdl.handle.net/1721.1/116864
dc.description.abstractSuper-enhancers are an emerging subclass of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here, we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancer-directed cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAs associated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and an unrecognized higher-order property of super-enhancers in RNA processing beyond transcription. Keywords: microRNA; super-enhancer; broad H3K4me3 domain; Drosha; DGCR8; Brd4; canceren_US
dc.description.sponsorshipUnited States. Public Health Service (Grant R01-CA133404)en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (Grant P30-CA14051)en_US
dc.publisherElsevieren_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/J.CELL.2017.02.015en_US
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs Licenseen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.sourcePMCen_US
dc.titleSuper-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysisen_US
dc.typeArticleen_US
dc.identifier.citationSuzuki, Hiroshi I. et al. “Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis.” Cell 168, 6 (March 2017): 1000–1014 © 2017 Elsevier Incen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentKoch Institute for Integrative Cancer Research at MITen_US
dc.contributor.mitauthorSuzuki, Hiroshi
dc.contributor.mitauthorYoung, Richard A
dc.contributor.mitauthorSharp, Phillip A
dc.relation.journalCellen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2018-07-09T15:12:40Z
dspace.orderedauthorsSuzuki, Hiroshi I.; Young, Richard A.; Sharp, Phillip A.en_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0001-8855-8647
dc.identifier.orcidhttps://orcid.org/0000-0003-1465-1691
mit.licensePUBLISHER_CCen_US


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