PXD030212

PXD030212 is an original dataset announced via ProteomeXchange.

Title	Mediator Kinase Complexes Regulates ATOH1-Dependent Intestinal Differentiation
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_08:31:22.284.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD030212
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Pouya Faridi
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-06 04:08:50	ID requested
1	2023-03-10 14:31:58	announced
⏵ 2	2023-11-14 08:31:23	announced	2023-11-14: Updated project metadata.

10.6019/PXD030212;

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: Phosphoproetomics. CDK8, CDK19

Pouya Faridi
contact affiliation	Head, Translational Antigen Discovery Lab Department of Medicine/ School of Clinical Sciences at Monash Health Monash University Level 7, TRF Building, Monash Medical Centre 246 Clayton Road Clayton VIC 3168 Australia M: +61 415126562
contact email	pouya.faridi@monash.edu
lab head
Pouya Faridi
contact affiliation	Monash University
contact email	pouya.faridi@monash.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD030212
     1. Label: PRIDE project
     2. Name: Mediator Kinase Complexes Regulates ATOH1-Dependent Intestinal Differentiation