Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
| Published: |
National Academy of Sciences
2012
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| Online Access: | http://hdl.handle.net/1721.1/74656 |
| _version_ | 1826196258644033536 |
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| author | Kubicek, Stefan Gilbert, Joshua C. Fomina-Yadlin, Dina Gitlin, Alexander D. Yuan, Yuan Wagner, Florence F. Holson, Edward B. Luo, Tuoping Lewis, Timothy A. Taylor, Bradley Gupta, Supriya Shamji, Alykhan F. Wagner, Bridget K. Clemons, Paul A. Schreiber, Stuart L. |
| author2 | Howard Hughes Medical Institute |
| author_facet | Howard Hughes Medical Institute Kubicek, Stefan Gilbert, Joshua C. Fomina-Yadlin, Dina Gitlin, Alexander D. Yuan, Yuan Wagner, Florence F. Holson, Edward B. Luo, Tuoping Lewis, Timothy A. Taylor, Bradley Gupta, Supriya Shamji, Alykhan F. Wagner, Bridget K. Clemons, Paul A. Schreiber, Stuart L. |
| author_sort | Kubicek, Stefan |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T10:24:05Z |
| format | Article |
| id | mit-1721.1/74656 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:24:05Z |
| publishDate | 2012 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/746562024-06-24T18:55:53Z Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells Kubicek, Stefan Gilbert, Joshua C. Fomina-Yadlin, Dina Gitlin, Alexander D. Yuan, Yuan Wagner, Florence F. Holson, Edward B. Luo, Tuoping Lewis, Timothy A. Taylor, Bradley Gupta, Supriya Shamji, Alykhan F. Wagner, Bridget K. Clemons, Paul A. Schreiber, Stuart L. Howard Hughes Medical Institute Kubicek, Stefan Fomina-Yadlin, Dina Yuan, Yuan Schreiber, Stuart L. 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. National Institute of General Medical Sciences (U.S.) (Grant GM38627) 2012-11-15T20:17:26Z 2012-11-15T20:17:26Z 2012-04 2011-11 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/74656 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 http://dx.doi.org/10.1073/pnas.1201079109 Proceedings of the National Academy of Sciences 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. application/pdf National Academy of Sciences PNAS |
| spellingShingle | Kubicek, Stefan Gilbert, Joshua C. Fomina-Yadlin, Dina Gitlin, Alexander D. Yuan, Yuan Wagner, Florence F. Holson, Edward B. Luo, Tuoping Lewis, Timothy A. Taylor, Bradley Gupta, Supriya Shamji, Alykhan F. Wagner, Bridget K. Clemons, Paul A. Schreiber, Stuart L. Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells |
| title | Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells |
| title_full | Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells |
| title_fullStr | Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells |
| title_full_unstemmed | Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells |
| title_short | Chromatin-targeting small molecules cause class-specific transcriptional changes in pancreatic endocrine cells |
| title_sort | chromatin targeting small molecules cause class specific transcriptional changes in pancreatic endocrine cells |
| url | http://hdl.handle.net/1721.1/74656 |
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