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dc.contributor.authorVerdine, Vanessa K.
dc.contributor.authorAguet, Francois
dc.contributor.authorFulco, Charles P.
dc.contributor.authorTseng, Yuen-Yi
dc.contributor.authorBoehm, Jesse S.
dc.contributor.authorJoung, Julia
dc.contributor.authorEngreitz, Jesse Michael
dc.contributor.authorKonermann, Silvana M
dc.contributor.authorGootenberg, Jonathan S
dc.contributor.authorSanjana, Neville E
dc.contributor.authorWright, Jason
dc.contributor.authorYoon, Charles
dc.contributor.authorLander, Eric Steven
dc.contributor.authorZhang, Feng
dc.contributor.authorAbudayyeh, Omar O.
dc.date.accessioned2018-02-14T14:36:28Z
dc.date.available2018-02-14T14:36:28Z
dc.date.issued2017-08
dc.date.submitted2017-01
dc.identifier.issn0028-0836
dc.identifier.issn1476-4687
dc.identifier.urihttp://hdl.handle.net/1721.1/113649
dc.description.abstractMammalian genomes contain thousands of loci that transcribe long noncoding RNAs (lncRNAs), some of which are known to carry out critical roles in diverse cellular processes through a variety of mechanisms. Although some lncRNA loci encode RNAs that act non-locally (in trans), there is emerging evidence that many lncRNA loci act locally (in cis) to regulate the expression of nearby genes—for example, through functions of the lncRNA promoter, transcription, or transcript itself. Despite their potentially important roles, it remains challenging to identify functional lncRNA loci and distinguish among these and other mechanisms. Here, to address these challenges, we developed a genome-scale CRISPR–Cas9 activation screen that targets more than 10,000 lncRNA transcriptional start sites to identify noncoding loci that influence a phenotype of interest. We found 11 lncRNA loci that, upon recruitment of an activator, mediate resistance to BRAF inhibitors in human melanoma cells. Most candidate loci appear to regulate nearby genes. Detailed analysis of one candidate, termed EMICERI, revealed that its transcriptional activation resulted in dosage-dependent activation of four neighbouring protein-coding genes, one of which confers the resistance phenotype. Our screening and characterization approach provides a CRISPR toolkit with which to systematically discover the functions of noncoding loci and elucidate their diverse roles in gene regulation and cellular function.en_US
dc.description.sponsorshipNational Human Genome Research Institute (U.S.) (Grant R00-HG008171)en_US
dc.description.sponsorshipNational Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Grant F32-DK096822)en_US
dc.description.sponsorshipNational Institute of Mental Health (U.S.) (Grant 5DP1-MH100706)en_US
dc.description.sponsorshipNational Institute of Mental Health (U.S.) (Grant 1R01-MH110049)en_US
dc.language.isoen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofhttp://dx.doi.org/10.1038/nature23451en_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.sourceProf. Zhang via Courtney Crummetten_US
dc.titleGenome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhooden_US
dc.typeArticleen_US
dc.identifier.citationJoung, Julia et al. “Genome-Scale Activation Screen Identifies a lncRNA Locus Regulating a Gene Neighbourhood.” Nature 548, 7667 (August 2017): 343–346en_US
dc.contributor.departmentHarvard University--MIT Division of Health Sciences and Technologyen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciencesen_US
dc.contributor.departmentMcGovern Institute for Brain Research at MITen_US
dc.contributor.approverZhang, Fengen_US
dc.contributor.mitauthorJoung, Julia
dc.contributor.mitauthorEngreitz, Jesse Michael
dc.contributor.mitauthorKonermann, Silvana M
dc.contributor.mitauthorAbudayyeh, Omar Osama
dc.contributor.mitauthorGootenberg, Jonathan S
dc.contributor.mitauthorSanjana, Neville E
dc.contributor.mitauthorWright, Jason
dc.contributor.mitauthorYoon, Charles
dc.contributor.mitauthorLander, Eric Steven
dc.contributor.mitauthorZhang, Feng
dc.relation.journalNatureen_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
dspace.orderedauthorsJoung, Julia; Engreitz, Jesse M.; Konermann, Silvana; Abudayyeh, Omar O.; Verdine, Vanessa K.; Aguet, Francois; Gootenberg, Jonathan S.; Sanjana, Neville E.; Wright, Jason B.; Fulco, Charles P.; Tseng, Yuen-Yi; Yoon, Charles H.; Boehm, Jesse S.; Lander, Eric S.; Zhang, Fengen_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0001-6656-5002
dc.identifier.orcidhttps://orcid.org/0000-0002-5754-1719
dc.identifier.orcidhttps://orcid.org/0000-0001-7915-1685
dc.identifier.orcidhttps://orcid.org/0000-0002-7979-3220
dc.identifier.orcidhttps://orcid.org/0000-0003-2782-2509
mit.licensePUBLISHER_POLICYen_US


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