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

doi:10.1172/JCI158593

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 journal › Article › Research › peer-review

3 Citations (Scopus)

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 language	English
Article number	e158593
Number of pages	15
Journal	The Journal of Clinical Investigation
Volume	132
Issue number	20
DOIs	https://doi.org/10.1172/JCI158593
Publication status	Published - 17 Oct 2022

Access to Document

10.1172/JCI158593

Cite this

Dannappel, M. V., Zhu, D., Sun, X., Chua, H. K., Poppelaars, M., Suehiro, M., Khadka, S., Lim Kam Sian, T. C. C., Sooraj, D., Loi, M., Gao, H., Croagh, D., Daly, R. J., Faridi, P., Boyer, T. G., & Firestein, R. (2022). CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF. The Journal of Clinical Investigation, 132(20), Article e158593. https://doi.org/10.1172/JCI158593

@article{4c2389b610844cdf88143b10ffbcd179,

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 {Lim Kam Sian}, {Terry C.C.} 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",

volume = "132",

journal = "The Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "20",

}

Dannappel, MV, Zhu, D, Sun, X, Chua, HK, Poppelaars, M, Suehiro, M, Khadka, S, Lim Kam Sian, TCC, Sooraj, D, Loi, M, Gao, H, Croagh, D , Daly, RJ , Faridi, P, Boyer, TG & Firestein, R 2022, 'CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF', The Journal of Clinical Investigation, vol. 132, no. 20, e158593. https://doi.org/10.1172/JCI158593

TY - JOUR

T1 - CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF

AU - Dannappel, Marius V.

AU - Zhu, Danxi

AU - Sun, Xin

AU - Chua, Hui Kheng

AU - Poppelaars, Marle

AU - Suehiro, Monica

AU - Khadka, Subash

AU - Lim Kam Sian, Terry C.C.

AU - Sooraj, Dhanya

AU - Loi, Melissa

AU - Gao, Hugh

AU - Croagh, Daniel

AU - Daly, Roger J.

AU - Faridi, Pouya

AU - Boyer, Thomas G.

AU - Firestein, Ron

N1 - 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’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: © 2022 American Society for Clinical Investigation. All rights reserved.

PY - 2022/10/17

Y1 - 2022/10/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85140144366&partnerID=8YFLogxK

U2 - 10.1172/JCI158593

DO - 10.1172/JCI158593

M3 - Article

C2 - 36006697

AN - SCOPUS:85140144366

SN - 0021-9738

VL - 132

JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

IS - 20

M1 - e158593

ER -

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

Abstract

Access to Document

Other files and links

Mediator kinase as a therapeutic target for Wnt/B-catenin dependent malignancies

Histology Platform

Monash Proteomics & Metabolomics Facility

Research Cloud

Cite this

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

Abstract

Access to Document

Other files and links

Projects

Mediator kinase as a therapeutic target for Wnt/B-catenin dependent malignancies

Equipment

Histology Platform

Monash Proteomics & Metabolomics Facility

Research Cloud

Cite this