Scientific Publications

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

Publication TypeJournal Article
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, and Schreiber SL
AbstractUnder 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.
Year of Publication2012
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue14
Pages5364-9
Date Published (YYYY/MM/DD)2012/04/03
ISSN Number0027-8424
DOI10.1073/pnas.1201079109
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/22434908?dopt=Abstract