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Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells

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dc.contributor.author Kubicek, Stefan
dc.contributor.author Gilbert, Joshua C.
dc.contributor.author Fomina-Yadlin, Dina
dc.contributor.author Gitlin, Alexander D.
dc.contributor.author Yuan, Yuan
dc.contributor.author Wagner, Florence F.
dc.contributor.author Holson, Edward B.
dc.contributor.author Luo, Tuoping
dc.contributor.author Lewis, Timothy A.
dc.contributor.author Taylor, Bradley
dc.contributor.author Gupta, Supriya
dc.contributor.author Shamji, Alykhan F.
dc.contributor.author Wagner, Bridget K.
dc.contributor.author Clemons, Paul A.
dc.contributor.author Schreiber, Stuart L.
dc.date.accessioned 2012-11-15T20:17:26Z
dc.date.available 2012-11-15T20:17:26Z
dc.date.issued 2012-04
dc.date.submitted 2011-11
dc.identifier.issn 0027-8424
dc.identifier.issn 1091-6490
dc.identifier.uri http://hdl.handle.net/1721.1/74656
dc.description.abstract Under the instruction of cell-fate–determining, DNA-binding transcription factors, chromatin-modifying enzymes mediate and maintain cell states throughout development in multicellular organisms. Currently, small molecules modulating the activity of several classes of chromatin-modifying enzymes are available, including clinically approved histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors. We describe the genome-wide expression changes induced by 29 compounds targeting HDACs, DNMTs, histone lysine methyltransferases (HKMTs), and protein arginine methyltransferases (PRMTs) in pancreatic α- and β-cell lines. HDAC inhibitors regulate several hundred transcripts irrespective of the cell type, with distinct clusters of dissimilar activity for hydroxamic acids and orthoamino anilides. In contrast, compounds targeting histone methyltransferases modulate the expression of restricted gene sets in distinct cell types. For example, we find that G9a/GLP methyltransferase inhibitors selectively up-regulate the cholesterol biosynthetic pathway in pancreatic but not liver cells. These data suggest that, despite their conservation across the entire genome and in different cell types, chromatin pathways can be targeted to modulate the expression of selected transcripts. en_US
dc.description.sponsorship National Institute of General Medical Sciences (U.S.) (Grant GM38627) en_US
dc.language.iso en_US
dc.publisher National Academy of Sciences en_US
dc.relation.isversionof http://dx.doi.org/10.1073/pnas.1201079109 en_US
dc.rights Article 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.source PNAS en_US
dc.title Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells en_US
dc.type Article en_US
dc.identifier.citation Kubicek, S. et al. “Chromatin-targeting Small Molecules Cause Class-specific Transcriptional Changes in Pancreatic Endocrine Cells.” Proceedings of the National Academy of Sciences 109.14 (2012): 5364–5369. ©2012 by the National Academy of Sciences en_US
dc.contributor.department Howard Hughes Medical Institute en_US
dc.contributor.mitauthor Kubicek, Stefan
dc.contributor.mitauthor Fomina-Yadlin, Dina
dc.contributor.mitauthor Yuan, Yuan
dc.contributor.mitauthor Schreiber, Stuart L.
dc.relation.journal Proceedings of the National Academy of Sciences en_US
dc.identifier.mitlicense PUBLISHER_POLICY en_US
dc.eprint.version Final published version en_US
dc.type.uri http://purl.org/eprint/type/JournalArticle en_US
eprint.status http://purl.org/eprint/status/PeerReviewed en_US
dspace.orderedauthors Kubicek, S.; Gilbert, J. C.; Fomina-Yadlin, D.; Gitlin, A. D.; Yuan, Y.; Wagner, F. F.; Holson, E. B.; Luo, T.; Lewis, T. A.; Taylor, B.; Gupta, S.; Shamji, A. F.; Wagner, B. K.; Clemons, P. A.; Schreiber, S. L. en


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