Proteomics

Dataset Information

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Colorectal Cancer Organoid Proteomics


ABSTRACT: Cyclin Dependent Kinases CDK8 and CDK19 (Mediator kinase) are regulatory components of the Mediator complex, a highly conserved complex that fine tunes transcriptional output. While Mediator kinase has been implicated in the transcriptional control of key pathways necessary for development and growth, its function in vivo has not been well described. Herein, we report the consequences of complete ablation of both Cdk8/19 on tissue homeostasis. We show that intestinal epithelial specific deletion of Mediator kinase leads to a distinct defect in secretory progenitor differentiation with broad loss of the intestinal secretory cell types. Using a phospho-proteogenomic approach, we show that the Cdk8/19 kinase module interacts with and phosphorylates components of the chromatin remodeling complex Swi/Snf in intestinal epithelial cells. Genomic localisation of Swi/Snf and Mediator shows Cdk8/19-dependent genomic binding at distinct super-enhancer loci within key lineage specification genes, including the master regulator of secretory differentiation ATOH1. Using CRISPRi/CRISPRa, we identify a distinct Mediator-Swi/Snf bound enhancer element that is necessary and sufficient for ATOH1 expression in a Mediator-kinase dependent manner. As such, these studies uncover a newly described transcriptional mechanism of ATOH1-dependent intestinal cell specification that is dependent on the coordinated interaction of the chromatin remodeling complex Swi/Snf and Mediator complex.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Colon

SUBMITTER: Terry Lim  

LAB HEAD: Ron Firestein

PROVIDER: PXD030256 | Pride | 2023-03-11

REPOSITORIES: Pride

Dataset's files

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HF1TL20210125_Marius_WP_E1.raw Raw
HF1TL20210125_Marius_WP_E2.raw Raw
HF1TL20210125_Marius_WP_E3.raw Raw
HF1TL20210125_Marius_WP_T1.raw Raw
HF1TL20210125_Marius_WP_T2.raw Raw
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Publications

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

Dannappel Marius V MV   Zhu Danxi D   Sun Xin X   Chua Hui Kheng HK   Poppelaars Marle M   Suehiro Monica M   Khadka Subash S   Lim Kam Sian Terry Cc TC   Sooraj Dhanya D   Loi Melissa M   Gao Hugh H   Croagh Daniel D   Daly Roger J RJ   Faridi Pouya P   Boyer Thomas G TG   Firestein Ron R  

The Journal of clinical investigation 20221017 20


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 d  ...[more]

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