dc.contributor.author | Suzuki, Hiroshi | |
dc.contributor.author | Young, Richard A. | |
dc.contributor.author | Sharp, Phillip A. | |
dc.date.accessioned | 2018-07-10T14:44:20Z | |
dc.date.available | 2018-07-10T14:44:20Z | |
dc.date.issued | 2017-03 | |
dc.date.submitted | 2017-02 | |
dc.identifier.issn | 0092-8674 | |
dc.identifier.issn | 1097-4172 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/116864 | |
dc.description.abstract | Super-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; cancer | en_US |
dc.description.sponsorship | United States. Public Health Service (Grant R01-CA133404) | en_US |
dc.description.sponsorship | National Cancer Institute (U.S.) (Grant P30-CA14051) | en_US |
dc.publisher | Elsevier | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1016/J.CELL.2017.02.015 | en_US |
dc.rights | Creative Commons Attribution-NonCommercial-NoDerivs License | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | en_US |
dc.source | PMC | en_US |
dc.title | Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Suzuki, Hiroshi I. et al. “Super-Enhancer-Mediated RNA Processing Revealed by Integrative MicroRNA Network Analysis.” Cell 168, 6 (March 2017): 1000–1014 © 2017 Elsevier Inc | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biology | en_US |
dc.contributor.department | Koch Institute for Integrative Cancer Research at MIT | en_US |
dc.contributor.mitauthor | Suzuki, Hiroshi | |
dc.contributor.mitauthor | Young, Richard A | |
dc.contributor.mitauthor | Sharp, Phillip A | |
dc.relation.journal | Cell | en_US |
dc.eprint.version | Author's final manuscript | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2018-07-09T15:12:40Z | |
dspace.orderedauthors | Suzuki, Hiroshi I.; Young, Richard A.; Sharp, Phillip A. | en_US |
dspace.embargo.terms | N | en_US |
dc.identifier.orcid | https://orcid.org/0000-0001-8855-8647 | |
dc.identifier.orcid | https://orcid.org/0000-0003-1465-1691 | |
mit.license | PUBLISHER_CC | en_US |