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dc.contributor.authorLessing, Derek
dc.contributor.authorDial, Thomas O.
dc.contributor.authorWei, Chunyao
dc.contributor.authorPayer, Bernhard
dc.contributor.authorCarrette, Lieselot L. G.
dc.contributor.authorKesner, Barry
dc.contributor.authorSzanto, Attila
dc.contributor.authorJadhav, Ajit
dc.contributor.authorMaloney, David J.
dc.contributor.authorSimeonov, Anton
dc.contributor.authorTheriault, Jimmy
dc.contributor.authorHasaka, Thomas
dc.contributor.authorBedalov, Antonio
dc.contributor.authorBartolomei, Marisa S.
dc.contributor.authorLee, Jeannie T.
dc.date.accessioned2017-09-13T19:38:24Z
dc.date.available2017-09-13T19:38:24Z
dc.date.issued2016-11
dc.date.submitted2016-07
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/111199
dc.description.abstractX-chromosome inactivation is a mechanism of dosage compensation in which one of the two X chromosomes in female mammals is transcriptionally silenced. Once established, silencing of the inactive X (Xi) is robust and difficult to reverse pharmacologically. However, the Xi is a reservoir of >1,000 functional genes that could be potentially tapped to treat X-linked disease. To identify compounds that could reactivate the Xi, here we screened ∼367,000 small molecules in an automated high-content screen using an Xi-linked GFP reporter in mouse fibroblasts. Given the robust nature of silencing, we sensitized the screen by “priming” cells with the DNA methyltransferase inhibitor, 5-aza-2′-deoxycytidine (5azadC). Compounds that elicited GFP activity include VX680, MLN8237, and 5azadC, which are known to target the Aurora kinase and DNA methylation pathways. We demonstrate that the combinations of VX680 and 5azadC, as well as MLN8237 and 5azadC, synergistically up-regulate genes on the Xi. Thus, our work identifies a synergism between the DNA methylation and Aurora kinase pathways as being one of interest for possible pharmacological reactivation of the Xi.en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1617597113en_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.titleA high-throughput small molecule screen identifies synergism between DNA methylation and Aurora kinase pathways for X reactivationen_US
dc.typeArticleen_US
dc.identifier.citationLessing, Derek et al. “A High-Throughput Small Molecule Screen Identifies Synergism Between DNA Methylation and Aurora Kinase Pathways for X Reactivation.” Proceedings of the National Academy of Sciences 113, 50 (December 2016): 14366–14371 © 2016 National Academy of Sciencesen_US
dc.contributor.departmentBroad Institute of MIT and Harvarden_US
dc.contributor.mitauthorTheriault, Jimmy
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.orderedauthorsLessing, Derek; Dial, Thomas O.; Wei, Chunyao; Payer, Bernhard; Carrette, Lieselot L. G.; Kesner, Barry; Szanto, Attila; Jadhav, Ajit; Maloney, David J.; Simeonov, Anton; Theriault, Jimmy; Hasaka, Thomas; Bedalov, Antonio; Bartolomei, Marisa S.; Lee, Jeannie T.en_US
dspace.embargo.termsNen_US
mit.licensePUBLISHER_POLICYen_US


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