The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B
Modulation of alternative pre-mRNA splicing is a potential approach to therapeutic targeting for a variety of human diseases. We investigated the mechanism by which digitoxin, a member of the cardiotonic steroid class of drugs, regulates alternative splicing. Transcriptome-wide analysis identified a...
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| Format: | Article |
| Language: | en_US |
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Cold Spring Harbor Laboratory Press
2014
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| Online Access: | http://hdl.handle.net/1721.1/84678 |
| _version_ | 1811076239946940416 |
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| author | Anderson, Erik S. Lin, Chia-Ho Xiao, Xinshu Stoilov, Peter Black, Douglas L. Burge, Christopher B |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Anderson, Erik S. Lin, Chia-Ho Xiao, Xinshu Stoilov, Peter Black, Douglas L. Burge, Christopher B |
| author_sort | Anderson, Erik S. |
| collection | MIT |
| description | Modulation of alternative pre-mRNA splicing is a potential approach to therapeutic targeting for a variety of human diseases. We investigated the mechanism by which digitoxin, a member of the cardiotonic steroid class of drugs, regulates alternative splicing. Transcriptome-wide analysis identified a large set of alternative splicing events that change after digitoxin treatment. Within and adjacent to these regulated exons, we identified enrichment of potential binding sites for the splicing factors SRp20 (SRSF3/SFRS3) and Tra2-β (SFRS10/TRA2B). We further find that both of these proteins are depleted from cells by digitoxin treatment. Characterization of SRp20 and Tra2-β splicing targets revealed that many, but not all, digitoxin-induced splicing changes can be attributed to the depletion of one or both of these factors. Re-expression of SRp20 or Tra2-β after digitoxin treatment restores normal splicing of their targets, indicating that the digitoxin effect is directly due to these factors. These results demonstrate that cardiotonic steroids, long prescribed in the clinical treatment of heart failure, have broad effects on the cellular transcriptome through these and likely other RNA binding proteins. The approach described here can be used to identify targets of other potential therapeutics that act as alternative splicing modulators. |
| first_indexed | 2024-09-23T10:18:30Z |
| format | Article |
| id | mit-1721.1/84678 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:18:30Z |
| publishDate | 2014 |
| publisher | Cold Spring Harbor Laboratory Press |
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| spelling | mit-1721.1/846782022-09-30T20:15:34Z The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B Anderson, Erik S. Lin, Chia-Ho Xiao, Xinshu Stoilov, Peter Black, Douglas L. Burge, Christopher B Massachusetts Institute of Technology. Department of Biology Burge, Christopher B. Modulation of alternative pre-mRNA splicing is a potential approach to therapeutic targeting for a variety of human diseases. We investigated the mechanism by which digitoxin, a member of the cardiotonic steroid class of drugs, regulates alternative splicing. Transcriptome-wide analysis identified a large set of alternative splicing events that change after digitoxin treatment. Within and adjacent to these regulated exons, we identified enrichment of potential binding sites for the splicing factors SRp20 (SRSF3/SFRS3) and Tra2-β (SFRS10/TRA2B). We further find that both of these proteins are depleted from cells by digitoxin treatment. Characterization of SRp20 and Tra2-β splicing targets revealed that many, but not all, digitoxin-induced splicing changes can be attributed to the depletion of one or both of these factors. Re-expression of SRp20 or Tra2-β after digitoxin treatment restores normal splicing of their targets, indicating that the digitoxin effect is directly due to these factors. These results demonstrate that cardiotonic steroids, long prescribed in the clinical treatment of heart failure, have broad effects on the cellular transcriptome through these and likely other RNA binding proteins. The approach described here can be used to identify targets of other potential therapeutics that act as alternative splicing modulators. National Institutes of Health (U.S.) (grant 4F30AG033993) National Institutes of Health (U.S.) (grant R01 GM08431) Howard Hughes Medical Institute (Investigator) 2014-02-07T16:39:22Z 2014-02-07T16:39:22Z 2012-03 2012-02 Article http://purl.org/eprint/type/JournalArticle 1355-8382 http://hdl.handle.net/1721.1/84678 Anderson, E. S., C.-H. Lin, X. Xiao, P. Stoilov, C. B. Burge, and D. L. Black. “The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B.” RNA 18, no. 5 (April 16, 2012): 1041-1049. © 2012 RNA Society. en_US http://dx.doi.org/10.1261/rna.032912.112 RNA Creative Commons Attribution-Non-Commercial 3.0 (CC-BY-NC) http://creativecommons.org/licenses/by-nc/3.0/ application/pdf Cold Spring Harbor Laboratory Press Cold Spring Harbor Laboratory Press |
| spellingShingle | Anderson, Erik S. Lin, Chia-Ho Xiao, Xinshu Stoilov, Peter Black, Douglas L. Burge, Christopher B The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B |
| title | The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B |
| title_full | The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B |
| title_fullStr | The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B |
| title_full_unstemmed | The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B |
| title_short | The cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors SRSF3 and TRA2B |
| title_sort | cardiotonic steroid digitoxin regulates alternative splicing through depletion of the splicing factors srsf3 and tra2b |
| url | http://hdl.handle.net/1721.1/84678 |
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