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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1201079109

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

Publication TypeJournal Article
Year of Publication2012
AuthorsKubicek, S, Gilbert, JC, Fomina-Yadlin, D, Gitlin, AD, Yuan, Y, Wagner, FF, Holson, EB, Luo, T, Lewis, TA, Taylor, B, Gupta, S, Shamji, AF, Wagner, BK, Clemons, PA, Schreiber, SL
JournalProc Natl Acad Sci U S A
Date Published2012 Apr 03
KeywordsCell Line, Chromatin, Down-Regulation, Gene Expression, Histone Deacetylase Inhibitors, Humans, Pancreas, Transcription, Genetic, Up-Regulation

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.


Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22434908
PubMed Central IDPMC3325696
Grant ListR37 GM038627 / GM / NIGMS NIH HHS / United States
DP2 DK083048 / DK / NIDDK NIH HHS / United States
R01 GM038627 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
GM38627 / GM / NIGMS NIH HHS / United States
DP2-DK083048 / DK / NIDDK NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States