CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere158593
JournalJournal of Clinical Investigation
Volume132
Issue number20
DOIs
StatePublished - Oct 17 2022

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint

Dive into the research topics of 'CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF'. Together they form a unique fingerprint.

Cite this