CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF.
Gastroenterology
Genetics
Molecular genetics
Mouse models
Oncogenes
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
17 10 2022
17 10 2022
Historique:
received:
19
01
2022
accepted:
23
08
2022
pubmed:
26
8
2022
medline:
19
10
2022
entrez:
25
8
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 36006697
pii: 158593
doi: 10.1172/JCI158593
pmc: PMC9566890
doi:
pii:
Substances chimiques
Chromatin
0
Cyclins
0
Transcription Factors
0
Sucrose
57-50-1
CDK19 protein, human
EC 2.7.11.22
CDK8 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 8
EC 2.7.11.22
Cyclin-Dependent Kinases
EC 2.7.11.22
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NICHD NIH HHS
ID : R01 HD087417
Pays : United States
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