@article{9ed823b511264aa0a0ce864f239f4cc9,
title = "CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF",
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.",
author = "Dannappel, {Marius V.} and Danxi Zhu and Xin Sun and Chua, {Hui Kheng} and Marle Poppelaars and Monica Suehiro and Subash Khadka and Sian, {Terry C.C.Lim Kam} and Dhanya Sooraj and Melissa Loi and Hugh Gao and Daniel Croagh and Daly, {Roger J.} and Pouya Faridi and Boyer, {Thomas G.} and Ron Firestein",
note = "Funding Information: We are grateful to Helen Abud for sharing VillinCreERT2 and Apcfl/fl mice. The generation of Cdk19D173A mice used in this study was supported by the Australian Phenomics Network and the Australian Government through the National Collaborative Research Infrastructure Strategy program. We acknowledge the resources and technical assistance of the Monash BDI Organoid Program, Monash Biomedicine Discovery Institute, Victoria, Australia. Computational resources were supported by the R@CMon/ Monash Node of the NeCTAR Research Cloud, an initiative of the Australian Government{\textquoteright}s Super Science Scheme and the Education Investment Fund. We acknowledge the Monash Biomedical Proteomics Facility, Monash University, for the provision of mass spectrometry instrumentation and technical support. We acknowledge use of the facilities and technical assistance of Monash Histology Platform, Department of Anatomy and Developmental Biology, Monash University. Funding support was received from National Health and Medical Research Council (NHMRC) grant APP1129689. RF was supported by an NHMRC Senior Research Fellowship (GA22057). MVD was supported by a research fellowship from the German Research Foundation (DFG) and the Evans Family Foundation. DZ was supported by the China Scholarship Council (CSC; 201906230314). PF was supported by the Victorian Department of Health and Human Services acting through the Victorian Cancer Agency. Publisher Copyright: {\textcopyright} 2022 American Society for Clinical Investigation. All rights reserved.",
year = "2022",
month = oct,
day = "17",
doi = "10.1172/JCI158593",
language = "English (US)",
volume = "132",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "20",
}