CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF
Initiation and maintenance of transcriptional states are critical for controlling normal tissue homeostasis and differentiation. The cyclin dependent kinases CDK8 and CDK19 (Mediator kinases) are regulatory components of Mediator, a highly conserved complex that orchestrates enhancer-mediated transc...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-10-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI158593 |
| _version_ | 1827768244842266624 |
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| author | Marius V. Dannappel Danxi Zhu Xin Sun Hui Kheng Chua Marle Poppelaars Monica Suehiro Subash Khadka Terry C.C. Lim Kam Sian Dhanya Sooraj Melissa Loi Hugh Gao Daniel Croagh Roger J. Daly Pouya Faridi Thomas G. Boyer Ron Firestein |
| author_facet | Marius V. Dannappel Danxi Zhu Xin Sun Hui Kheng Chua Marle Poppelaars Monica Suehiro Subash Khadka Terry C.C. Lim Kam Sian Dhanya Sooraj Melissa Loi Hugh Gao Daniel Croagh Roger J. Daly Pouya Faridi Thomas G. Boyer Ron Firestein |
| author_sort | Marius V. Dannappel |
| collection | DOAJ |
| description | Initiation and maintenance of transcriptional states are critical for controlling normal tissue homeostasis and differentiation. The cyclin dependent kinases CDK8 and CDK19 (Mediator kinases) are regulatory components of Mediator, a highly conserved complex that orchestrates enhancer-mediated transcriptional output. While Mediator kinases have been implicated in the transcription of genes necessary for development and growth, its function in mammals has not been well defined. Using genetically defined models and pharmacological inhibitors, we showed that CDK8 and CDK19 function in a redundant manner to regulate intestinal lineage specification in humans and mice. The Mediator kinase module bound and phosphorylated key components of the chromatin remodeling complex switch/sucrose non-fermentable (SWI/SNF) in intestinal epithelial cells. Concomitantly, SWI/SNF and MED12-Mediator colocalized at distinct lineage-specifying enhancers in a CDK8/19–dependent manner. Thus, these studies reveal a transcriptional mechanism of intestinal cell specification, coordinated by the interaction between the chromatin remodeling complex SWI/SNF and Mediator kinase. |
| first_indexed | 2024-03-11T12:09:34Z |
| format | Article |
| id | doaj.art-3d46bbee8ab546fa96a8734f41d7728e |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:34Z |
| publishDate | 2022-10-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-3d46bbee8ab546fa96a8734f41d7728e2023-11-07T16:19:26ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-10-0113220CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNFMarius V. DannappelDanxi ZhuXin SunHui Kheng ChuaMarle PoppelaarsMonica SuehiroSubash KhadkaTerry C.C. Lim Kam SianDhanya SoorajMelissa LoiHugh GaoDaniel CroaghRoger J. DalyPouya FaridiThomas G. BoyerRon FiresteinInitiation and maintenance of transcriptional states are critical for controlling normal tissue homeostasis and differentiation. The cyclin dependent kinases CDK8 and CDK19 (Mediator kinases) are regulatory components of Mediator, a highly conserved complex that orchestrates enhancer-mediated transcriptional output. While Mediator kinases have been implicated in the transcription of genes necessary for development and growth, its function in mammals has not been well defined. Using genetically defined models and pharmacological inhibitors, we showed that CDK8 and CDK19 function in a redundant manner to regulate intestinal lineage specification in humans and mice. The Mediator kinase module bound and phosphorylated key components of the chromatin remodeling complex switch/sucrose non-fermentable (SWI/SNF) in intestinal epithelial cells. Concomitantly, SWI/SNF and MED12-Mediator colocalized at distinct lineage-specifying enhancers in a CDK8/19–dependent manner. Thus, these studies reveal a transcriptional mechanism of intestinal cell specification, coordinated by the interaction between the chromatin remodeling complex SWI/SNF and Mediator kinase.https://doi.org/10.1172/JCI158593GastroenterologyGenetics |
| spellingShingle | Marius V. Dannappel Danxi Zhu Xin Sun Hui Kheng Chua Marle Poppelaars Monica Suehiro Subash Khadka Terry C.C. Lim Kam Sian Dhanya Sooraj Melissa Loi Hugh Gao Daniel Croagh Roger J. Daly Pouya Faridi Thomas G. Boyer Ron Firestein CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF The Journal of Clinical Investigation Gastroenterology Genetics |
| title | CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF |
| title_full | CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF |
| title_fullStr | CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF |
| title_full_unstemmed | CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF |
| title_short | CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF |
| title_sort | cdk8 and cdk19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex swi snf |
| topic | Gastroenterology Genetics |
| url | https://doi.org/10.1172/JCI158593 |
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