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CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF
Marius V. Dannappel, … , Thomas G. Boyer, Ron Firestein
Marius V. Dannappel, … , Thomas G. Boyer, Ron Firestein
Published August 25, 2022
Citation Information: J Clin Invest. 2022;132(20):e158593. https://doi.org/10.1172/JCI158593.
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Research Article Gastroenterology Genetics Article has an altmetric score of 3

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

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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.

Authors

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

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Figure 4

Deletion of CDK8/19 blocks secretory progenitor cell differentiation.

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Deletion of CDK8/19 blocks secretory progenitor cell differentiation.
(A...
(A) MA plots show differentially expressed genes in CDK8iIEC-KO and CDK8iIEC-KO/Cdk19–/– intestinal organoids (vs. VillinCreERT2) and Cdk8fl/fl/Cdk19–/– organoids (vs. C57BL/6) 7 days after 4-OHT treatment. NS, not significant. (B) Heatmap depicts unique differentially expressed genes (DEGs) in organoids with the indicated genotypes 7 days after 4-OHT treatment. (C) GSEA for intestinal cell lineages shows normalized enrichment score (NES) comparing VillinCreERT2 and CDK8iIEC-KO/Cdk19–/– organoids. GC, goblet cells; PC, Paneth cells; TC, tuft cells; EEC, enteroendocrine cells; ISC, intestinal stem cells. (D) GSEA for intestinal cell lineages shows NES comparing VillinCreERT2 and CDK8iIEC-KO/Cdk19–/– small intestinal IECs. (E) Intestinal cell lineage signature and gene expression cluster analysis in 4-OHT–treated VillinCreERT2/Cdk8fl/fl/Cdk19–/– organoids compared with EtOH controls at days 3, 5, 7, and 10 after treatment. Fisher’s exact test with Bonferroni correction. (F and G) qRT-PCR analysis of the indicated Paneth cell marker expression in intestinal organoids 7 days after 4-OHT treatment (F) and small intestinal IECs from mice (G). Mouse genotypes are color-coded and indicated below G. Unpaired 2-tailed t test and Mann-Whitney test. (H) Immunofluorescent staining and quantification of lysozyme in VillinCreERT2/Cdk8fl/fl/Cdk19–/– organoids 9 days after EtOH and 4-OHT treatment. EtOH, n = 52 crypts; 4-OHT, n = 65 crypts. Scale bars: 50 μm. Mann-Whitney test. Data represent mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.005, ****P ≤ 0.001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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