title: Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells.
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.
authors.affiliation: Howard Hughes Medical Institute, Cambridge, MA 02142, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Gilbert
authors.forename: Dina
authors.initials: D
authors.lastname: Fomina-Yadlin
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Gitlin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
authors.forename: Tuoping
authors.initials: T
authors.lastname: Luo
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Lewis
authors.forename: Bradley
authors.initials: B
authors.lastname: Taylor
authors.forename: Supriya
authors.initials: S
authors.lastname: Gupta
authors.forename: Alykhan F
authors.initials: AF
authors.lastname: Shamji
authors.forename: Bridget K
authors.initials: BK
authors.lastname: Wagner
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D015536:Down-Regulation; D015870:Gene Expression; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D010179:Pancreas / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors