PXD030256

PXD030256 is an original dataset announced via ProteomeXchange.

Title	Colorectal Cancer Organoid Proteomics
Description	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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:39:30.400.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Terry Lim
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-08 12:33:45	ID requested
1	2023-03-11 00:50:03	announced
⏵ 2	2023-11-14 08:39:32	announced	2023-11-14: Updated project metadata.

Dannappel MV, Zhu D, Sun X, Chua HK, Poppelaars M, Suehiro M, Khadka S, Lim Kam Sian TC, Sooraj D, Loi M, Gao H, Croagh D, Daly RJ, Faridi P, Boyer TG, Firestein R, CDK8 and CDK19 regulate intestinal differentiation and homeostasis via the chromatin remodeling complex SWI/SNF. J Clin Invest, 132(20):(2022) [pubmed]

submitter keyword: Mouse, Colorectal Cancer, Proteomics

Ron Firestein
contact affiliation	1 Hudson Institute of Medical Research, Clayton, VIC, Australia, 2 Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
contact email	ron.firestein@hudson.org.au
lab head
Terry Lim
contact affiliation	Monash University
contact email	terry.lim@monash.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD030256

PRIDE project URI

• PRIDE
  1. PXD030256
     1. Label: PRIDE project
     2. Name: Colorectal Cancer Organoid Proteomics