2. Academic Validation
  3. CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF

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

  • J Clin Invest. 2022 Oct 17;132(20):e158593. doi: 10.1172/JCI158593.
Marius V Dannappel 1 2,  Danxi Zhu 1 3,  Xin Sun 1 2,  Hui Kheng Chua 1 2,  Marle Poppelaars 1 2,  Monica Suehiro 1 2,  Subash Khadka 4,  Terry Cc Lim Kam Sian 5,  Dhanya Sooraj 1 2,  Melissa Loi 1 2,  Hugh Gao 1 3,  Daniel Croagh 6,  Roger J Daly 5,  Pouya Faridi 7,  Thomas G Boyer 4,  Ron Firestein 1 2
Affiliations

Affiliations

  • 1 Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
  • 2 Department of Molecular and Translational Science and.
  • 3 Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
  • 4 Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
  • 5 Cancer Program, Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology.
  • 6 School of Clinical Sciences at Monash Health, and.
  • 7 Department of Medicine, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
PMID: 36006697 DOI: 10.1172/JCI158593
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.

Keywords

Gastroenterology; Genetics; Molecular genetics; Mouse models; Oncogenes.

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