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Mediator facilitates transcription initiation at most promoters via a Tail-independent mechanism [ChEC-seq]

ABSTRACT: Mediator (MED) is a conserved factor with important roles in basal and activated transcription. Here, we investigate the genome-wide roles of yeast MED by rapid depletion of its activator-binding domain (Tail) and monitoring changes in nascent transcription. Rapid Tail depletion surprisingly reduces transcription from only a small subset of genes. At most of these Tail-dependent genes, in unperturbed conditions, MED is detected at both the UASs and promoters. In contrast, at most Tail-independent genes, we find MED primarily at promoters but not at the UASs. These results suggest that MED Tail and activator-mediated MED recruitment regulate only a small subset of genes. Further, we define three classes of genes that differ in PIC assembly pathways and the requirements for MED Tail, SAGA, TFIID and BET factors Bdf1/2. Our combined results have broad implications for the roles of MED, other coactivators, and mechanisms of transcriptional regulation at different gene classes.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE190774 | GEO | 2022/08/22

REPOSITORIES: GEO

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Mediator facilitates transcription initiation at most promoters via a Tail-independent mechanism [RNA-seq]

Project description:Mediator (MED) is a conserved factor with important roles in basal and activated transcription. Here, we investigate the genome-wide roles of yeast MED by rapid depletion of its activator-binding domain (Tail) and monitoring changes in nascent transcription. Rapid Tail depletion surprisingly reduces transcription from only a small subset of genes. At most of these Tail-dependent genes, in unperturbed conditions, MED is detected at both the UASs and promoters. In contrast, at most Tail-independent genes, we find MED primarily at promoters but not at the UASs. These results suggest that MED Tail and activator-mediated MED recruitment regulate only a small subset of genes. Further, we define three classes of genes that differ in PIC assembly pathways and the requirements for MED Tail, SAGA, TFIID and BET factors Bdf1/2. Our combined results have broad implications for the roles of MED, other coactivators, and mechanisms of transcriptional regulation at different gene classes.

2022-08-22 | GSE190777 | GEO

Mediator facilitates transcription initiation at most promoters via a Tail-independent mechanism [ChIP-seq]

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Large-scale reporter assay to assess expression and coactivator specificity of UAS-core promoter combinations [III]

Project description:Three general classes of yeast protein-coding genes are distinguished by their dependence on the transcription cofactors TFIID, SAGA and Mediator (MED) Tail, but little is known about whether this dependence is determined by the core promoter, Upstream activation sites (UAS), or other gene features. It is also unclear whether UASs can broadly activate transcription from the different promoter classes or whether efficient transcription requires matching UASs and promoters of similar gene class. Here we measure transcription and cofactor specificity for tens of thousands of UAS-core promoter combinations. We find that few UASs display strong core promoter specificity while most UASs can broadly activate promoters regardless of regulatory class. However, we find that matching UASs and promoters from the same gene class is generally important for optimal expression. We find that MED Tail and SAGA are dependent on the identity of both UAS and promoter while dependence on TFIID localizes to only the core promoter.

2023-03-17 | GSE227006 | GEO

Large-scale reporter assay to assess expression and coactivator specificity of UAS-core promoter combinations (RNA)

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Large-scale reporter assay to assess expression and coactivator specificity of UAS-core promoter combinations (DNA)

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BET family members Bdf1/2 modulate global transcription initiation and elongation in Saccharomyces cerevisiae (ChEC-Seq)

Project description:Human BET family members are promising targets in the therapy of cancer and immunoinflammatory diseases, but their mechanism of action and functional redundancies are poorly understood. Yeast BET factors Bdf1/2 were previously proposed to act as anchors for coactivator TFIID. We investigated their genome wide roles in transcription and found that, while they cooperate with TFIID at many genes, their contributions to transcription are often significantly different. Bdf1/2 co-occupy the majority of yeast promoters and affect preinitiation complex formation by participating in recruitment of TFIID, Mediator and basal factors to chromatin. Surprisingly, we discovered that hypersensitivity of genes to Bdf1/2 depletion results from combined defects in initiation of transcription and early elongation. Bdf1/2 are critical components of yeast transcriptional machinery with many functional similarities to human BET proteins, most notably Brd4.

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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

Connection of core and and tail Mediator modules restrains transcription from TFIID-dependent promoters [ChEC-seq]

Project description:The Mediator coactivator complex is divided into four modules: head, middle, tail, and kinase. Deletion of the architectural subunit Med16 separates core Mediator (cMed), comprising the head, middle, and scaffold (Med14), from the tail. However, the direct global effects of tail/cMed disconnection are unclear. We find that rapid depletion of Med16 downregulates genes that require the SAGA complex for full expression, consistent with their reported tail dependence, but also moderately overactivates TFIID-dependent genes in a manner partly dependent on the separated tail, which remains associated with upstream activating sequences. Suppression of TBP dynamics via removal of the Mot1 ATPase partially restores normal transcriptional activity to Med16-depleted cells, suggesting that cMed/tail separation results in an imbalance in the levels PIC formation at SAGA-requiring and TFIID-dependent genes. We suggest that the preferential regulation of SAGA-requiring genes by tailed Mediator helps maintain a proper balance of transcription between these genes and those more dependent on TFIID.

2021-07-30 | GSE169746 | GEO

Connection of core and and tail Mediator modules restrains transcription from TFIID-dependent promoters [ChEC-seq Med16-AID]

2021-07-30 | GSE179765 | GEO

An IDR-dependent mechanism for nuclear receptor control of mediator interaction with RNA polymerase II

Project description:We investigated modulation of metazoan MED interaction with RNA polymerase II (Pol II) by antagonistic effects of the MED26 subunit and the Cdk8 kinase module (CKM), both of which associate dynamically with MED. Results from in vivo studies point to a general and important role of MED26 in transcription, connected to Pol II recruitment. Analysis of CKM-MED and MED26-MED complexes by cryo-EM and crosslinking-mass spectrometry showed that CKM and MED26 have opposite effects on mMED association with Pol II (blocking and facilitating it, respectively), and revealed that the structural basis for their antagonistic interaction with MED relates to extended intrinsically-disordered regions (IDRs) in MED26 and the CKM subunit MED13 competing for interaction with MED. We found CKM-MED to be the preferred target of nuclear receptors (NRs), whose binding can initiate rearrangements of the MED13 IDR that allow MED26-dependent interaction of CKM-MED with the Pol II carboxy-terminal domain (CTD). Our results suggest that activators might play a critical role independent of MED recruitment, instead “activating” CKM-MED for CTD interaction in a MED26-dependent manner and, thus, controlling the start of preinitiation complex assembly. The presence of an intermediate state in which MED26 and the CTD II can interact with CKM-MED suggests a mechanism for fast, recruitment-independent activation connected to promoter-proximal Pol II pausing, with an activator enabling interaction between the originally inactive CKM-MED and a paused Pol II poised to initiate transcription. We found that CTD interaction with CKM-MED influences the subunit composition of the Tail module and this allostery suggests that the mechanism we propose could apply to non-NR activators targeting Tail subunits.

2024-08-19 | GSE233372 | GEO

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