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The Mediator kinase module regulates transcriptional memory after heat stress by resolving blocked RNA polymerase complexes

ABSTRACT: The Mediator kinase module regulates transcriptional memory after heat stress by resolving blocked RNA polymerase complexes

PROVIDER: PRJNA970811 | ENA |

REPOSITORIES: ENA

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The Mediator kinase module regulates transcriptional memory after heat stress by resolving blocked RNA polymerase complexes

Project description:In nature, plants are often exposed to recurring adverse environmental conditions. Acclimation to high temperature stress entails transcriptional responses that are mediated by heat-shock transcription factors (HSFs), and they are primed to better withstand subsequent stress events. This heat stress (HS)-induced transcriptional memory results in more efficient re-induction of transcription upon recurring HS. However, the mechanisms by which HSFs recruit and enact the transcriptional machinery remain unclear. Here, we identified two subunits of the kinase module of the Mediator transcriptional co-regulator complex, CDK8 and MED12, as regulators of HS memory in Arabidopsis thaliana. Enhanced re-induction of gene expression after recurrent HS and physiological HS memory, as well as H3K4 methylation are compromised in cdk8 and med12 mutants. HSFA2 interacts with CDK8 during and after HS and recruits it to memory gene loci, where CDK8 binds in the promoter but also the gene body, together with core Mediator and RNA polymerase II (Pol II). Our data suggest that CDK8 resolves stalled Pol II complexes or promotes efficient recycling for subsequent cycles of transcription. As HSFA2, CDK8 is largely dispensable for the initial induction of gene expression after HS and thus promotes transcriptional memory independently of HS-dependent primary gene induction. Our findings provide a model for the complex role of the Mediator kinase module during transcriptional memory in multicellular eukaryotes through interaction with transcription factors, chromatin modifications and promotion of Pol II productivity.

2023-12-12 | GSE232094 | GEO

Structural basis of the human transcriptional Mediator complex modulated by its dissociable Kinase module

Project description:The Mediator complex consists of a Core and a dissociable Kinase module. This project is to understand the binding mode between the Core and Kinase module. Both Mediator complex and its Kinase module were individually crosslinked and analyzed by XL-MS.

2024-11-21 | PXD044328 | Pride

Mammalian mediator structure and conformation regulation by the Tail module

Project description:The Mediator complex plays an essential and multi-faceted role in regulation of RNA polymerase II transcription in all eukaryotes. Structural analysis of yeast Mediator provided an understanding of the conserved core of the complex and its interaction with RNA polymerase II, but failed to reveal how Mediator might enable a response to interaction with transcription factors (TFs). Here we present an atomic model of mammalian (Mus musculus) Mediator, derived from a 4.0 Å resolution cryo-EM map of the complex. The mammalian Mediator structure reveals how the previously unresolved Tail module, which includes a number of metazoan specific subunits, modulates Mediator conformation and interactions. The structure also suggests how a bi-partite organization of TF-interacting subunits can be exploited to enable a Mediator mechanism that combines conformational control of molecular interactions and enhancement of transcription through phase separation and enhancer-specific recruitment

2020-03-30 | GSE145902 | GEO

Requirement for the Mediator kinase module for activation of super-enhancer associated genes in colon cancer cells

Project description:RNA sequencing of HCT116 colon cancer cells following single and combined depletions of Mediator kinase module subunits CDK8, CDK19, MED12, MED13 and MED13L and the BET family protein BRD4. The results provide insight into the shared and specific functions of kinase module subunits and BRD4 in regulation of expression of transcriptional programs including genes associated with cancer acquired super-enhancers.

2018-04-02 | E-MTAB-5873 | biostudies-arrayexpress

The Cdk8 kinase module regulates Mediator-RNA polymerase II interaction

Project description:The Cdk8 kinase module (CKM) is a dissociable part of the coactivator complex Mediator that regulates RNA polymerase II (Pol II transcription. The CKM has negative and positive functions in gene transcription that remain poorly understood at the mechanistic level. Here, we prepare recombinant CKM from the yeast Saccharomyces cerevisiae and show that it binds core Mediator (cMed) to sterically inhibit cMed binding to the Pol II preinitiation complex (PIC) in vitro. We further show that the Cdk8 kinase activity of CKM counteracts CKM-cMed interaction,thereby releasing CKM and enabling Mediator to bind the PIC. Finally, we report that the kinase activity of Cdk8 is required for gene activation during heat shock in vivo, but not under steady state growth conditions. These results converge with previous literature on a model for CKM function. In this model, CKM negatively regulates Mediator function at upstream activating sequences by preventing Mediator binding to the PIC at the promoter. During gene activation, Cdk8 kinase activity may release Mediator and allow its binding to the PIC, thereby stimulating transcription initiation and accounting for the positive function of CKM.

2021-06-16 | GSE161140 | GEO

The Cdk8 kinase module regulates Mediator-RNA polymerase II interaction

Project description:The Cdk8 kinase module regulates Mediator-RNA polymerase II interaction

| PRJNA675650 | ENA

Mammalian mediator structure and conformation regulation by the Tail module

Project description:Mammalian mediator structure and conformation regulation by the Tail module

| PRJNA608703 | ENA

Mediator Kinase Complexes Regulates ATOH1-Dependent Intestinal Differentiation

Project 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.

2023-03-10 | PXD030212 | Pride

Structure of Saccharomyces cerevisiae Mediator-RNA polymerase II pre-initiation complex for divergent transcription

Project description:This study has determined structure of transcription initiation complexes including a DNA-bound activator, RNA polymerase II (Pol II), and Mediator on a divergent promoter GAL80/SUT719 using a combination of cryo-EM and XL-MS analyses. Our cryo-EM single-particle analysis reveals a dimeric form of Med-PIC through the Mediator Tail module induced by the activator protein. Density of the upstream DNA bound to the Gal4-VP16 was identifiable along the Mediator Tail module, while XL-MS localized flexible regions that were not visible by cryo-EM analysis, such as activator-binding domains (ABDs and KIX).

2024-05-22 | PXD036149 | Pride

MYC, together with Cohesin and Mediator complexes, predetermines the sensitivity of gastrointestinal cancer to antifolate drugs

Project description:MYC, together with Cohesin and Mediator complexes, predetermines the sensitivity of gastrointestinal cancer to antifolate drugs

2019-11-19 | GSE123364 | GEO

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