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Mediator complex interaction partners organize the transcriptional network that defines neural stem cells

ABSTRACT: The Mediator complex regulates transcription by connecting enhancers to promoters. High Mediator binding density is one defining feature of so-called super enhancers, which regulate cell-identity genes and oncogenes. Protein interactions of Mediator may explain its role in these processes but have not been identified comprehensively. Here we purify Mediator from neural stem cells (NSCs) and identify 77 novel protein-protein interaction partners. We identified super enhancers in NSCs and show that Mediator-interacting chromatin modifiers colocalise with Mediator at enhancers and super enhancers. Three transcription factor families with high affinity for Mediator dominate enhancers and super enhancers in NSCs and can explain genome-wide Mediator localization. We identify E-box transcription factor Tcf4 as a key regulator in NSCs. Tcf4 interacts with Mediator, colocalises and correlates with Mediator at super enhancers and regulates other neural transcription factors via super enhancers. Our data suggest that high binding-affinity for Mediator is an important organizing feature in the transcriptional network that determines NSC identity.

ORGANISM(S): Mus musculus

PROVIDER: GSE109043 | GEO | 2019/04/01

REPOSITORIES: GEO

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Mediator complex interaction partners organize the transcriptional network that defines neural stem cells

Project description:Mediator complex regulates transcription by connecting enhancers to promoters. High Mediator binding density defines super enhancers, which regulate cell-identity genes and oncogenes. Protein interactions of Mediator may explain its role in these processes but have not been identified comprehensively. Here we purify Mediator from neural stem cells (NSCs) and identify 75 protein-protein interaction partners. We identify super enhancers in NSCs and show that Mediator-interacting chromatin modifiers colocalise with Mediator at enhancers and super enhancers. Transcription factor families with high affinity for Mediator dominate enhancers and super enhancers and can explain genome-wide Mediator localization. We identify E-box transcription factor Tcf4 as a key regulator of NSCs. Tcf4 interacts with Mediator, colocalises with Mediator at super enhancers and regulates neurogenic transcription factor genes with super enhancers and broad H3K4me3 domains. Our data suggest that high binding-affinity for Mediator is an important organizing feature in the transcriptional network that determines NSC identity.

2019-05-06 | PXD013546 | Pride

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes [ChIP-Seq]

Project description:The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that the ESC master transcription factors and Mediator form “super-enhancers” at most genes known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4, Sox2, Nanog, Klf4, Esrrb and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in vivo and in reporter vectors. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. These results implicate super-enhancers in the control of mammalian cell identity and differentiation. ChIP-Seq and controls associated with Super-Enhancers in murine cell types

2013-02-13 | E-GEOD-44286 | biostudies-arrayexpress

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes [gene expression]

Project description:The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that the ESC master transcription factors and Mediator form M-bM-^@M-^\super-enhancersM-bM-^@M-^] at most genes known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4, Sox2, Nanog, Klf4, Esrrb and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in vivo and in reporter vectors. Reduced levels of Oct4 or Mediator cause preferential loss of expression of super-enhancer-associated genes relative to other genes, suggesting how changes in gene expression programs might be accomplished during development. In other more differentiated cells, super-enhancers containing cell-type-specific master transcription factors are also found at genes that define cell identity. These results implicate super-enhancers in the control of mammalian cell identity and differentiation. Time-course of gene expression following shRNA knockdown of Oct4 and Med12.

2013-02-13 | E-GEOD-44287 | biostudies-arrayexpress

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes

Project description:The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that these ESC master transcription factors and Mediator form M-bM-^@M-^\super-enhancersM-bM-^@M-^] at most genes that are known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4 and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in reporter vectors. ESC differentiation causes preferential loss of expression of super-enhancer -associated genes. Super-enhancers are also found at key cell identity genes in differentiated cells. These results implicate super-enhancers in the control of mammalian cell identity and differentiation and suggest that these elements might generally be used to identify genes that control cell-type specific gene expression programs in many mammalian cells. ChIP-Seq and RNA-seq of Med1 in ZHBTc4 ES during treatment with doxycycline. ChIP-Seq data of Med1 in 38B9 pro-B cells.

2013-01-02 | E-GEOD-42474 | biostudies-arrayexpress

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes [gene expression]

2013-02-13 | GSE44287 | GEO

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes [ChIP-Seq]

2013-02-13 | GSE44286 | GEO

Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers

Project description:Chromatin regulators have become highly attractive targets for cancer therapy, yet many of these regulators are expressed in a broad range of healthy cells and contribute generally to gene expression. An important conundrum has thus emerged: how can inhibition of a general regulator of gene expression produce selective effects at specific oncogenes? Here we investigate how inhibition of the transcriptional coactivator BRD4 (Bromodomain containing 4) leads to selective inhibition of disease-critical oncogenes in a highly malignant blood cancer, multiple myeloma (MM). We found that BRD4 generally occupies the promoter elements of active genes together with the Mediator coactivator, but remarkably high levels of these two coactivator proteins were associated with a small set of exceptionally large enhancers. These super-enhancers are associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impact genes with super-enhancers, including the c-MYC oncogene. Super-enhancers were found at key oncogenic drivers in many other tumor cells. Thus, super-enhancers can regulate oncogenic drivers in tumor cells, which in some cells can be preferentially disrupted by BRD4 inhibition, which in turn contributes to the selective transcriptional effects observed at these oncogenes. These observations have implications for the discovery of novel cancer therapeutics directed at components of super-enhancers in diverse tumor types. ChIP-Seq for chromatin regulators and RNA Polymerase II in multiple myeloma, glioblastoma multiforme, and small cell lung cancer

2013-01-02 | E-GEOD-42355 | biostudies-arrayexpress

Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers [Affymetrix]

Project description:Chromatin regulators have become highly attractive targets for cancer therapy, yet many of these regulators are expressed in a broad range of healthy cells and contribute generally to gene expression. An important conundrum has thus emerged: how can inhibition of a general regulator of gene expression produce selective effects at specific oncogenes? Here we investigate how inhibition of the transcriptional coactivator BRD4 (Bromodomain containing 4) leads to selective inhibition of disease-critical oncogenes in a highly malignant blood cancer, multiple myeloma (MM). We found that BRD4 generally occupies the promoter elements of active genes together with the Mediator coactivator, but remarkably high levels of these two coactivator proteins were associated with a small set of exceptionally large enhancers. These super-enhancers are associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impact genes with super-enhancers, including the c-MYC oncogene. Super-enhancers were found at key oncogenic drivers in many other tumor cells. Thus, super-enhancers can regulate oncogenic drivers in tumor cells, which in some cells can be preferentially disrupted by BRD4 inhibition, which in turn contributes to the selective transcriptional effects observed at these oncogenes. These observations have implications for the discovery of novel cancer therapeutics directed at components of super-enhancers in diverse tumor types. Gene expression profiling in multiple myeloma cells after BET-Bromodomain inhibition with JQ1

2013-03-07 | E-GEOD-44929 | biostudies-arrayexpress

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes [ChIP-Seq and RNA-seq]

Project description:The master transcription factors Oct4, Sox2 and Nanog bind enhancer elements and recruit the Mediator co-activator to activate much of the gene expression program of embryonic stem cells (ESCs). We report here that these ESC master transcription factors and Mediator form “super-enhancers” at most genes that are known to control the pluripotent state, including those encoding the master transcription factors themselves. These super-enhancers consist of extraordinarily large genomic domains occupied by exceptional amounts of Oct4 and Mediator. Super-enhancers stimulate considerably higher transcription than typical enhancers in reporter vectors. ESC differentiation causes preferential loss of expression of super-enhancer -associated genes. Super-enhancers are also found at key cell identity genes in differentiated cells. These results implicate super-enhancers in the control of mammalian cell identity and differentiation and suggest that these elements might generally be used to identify genes that control cell-type specific gene expression programs in many mammalian cells.

2013-01-02 | GSE42474 | GEO

Super-enhancers require enhancers and facilitators to fully activate gene expression [ATAC-seq]

Project description:Super-enhancers are compound regulatory elements which control expression of key cell-identity genes. They recruit high levels of tissue-specific transcription factors, co-activators such as the mediator complex, and they contact their target gene promoters with high frequency. Most super-enhancers contain multiple constituent regulatory elements, but it is unclear whether these elements have distinct roles in activating expression of their cognate genes. Here, through comprehensively rebuilding the endogenous α-globin super-enhancer, we show that super-enhancers comprise bioinformatically equivalent but functionally distinct element types: classical enhancers and facilitator elements. Facilitators have no intrinsic enhancer activity, yet in their absence, classical enhancers are unable to fully up-regulate their target genes. Without facilitators, classical enhancers exhibit reduced mediator recruitment, enhancer RNA transcription and enhancer-promoter interactions. Facilitators are interchangeable, but display functional hierarchy based on their position within a super-enhancer. Facilitators thus play an important role in potentiating super-enhancer activity and ensuring robust activation of target genes.

2023-12-31 | GSE219056 | GEO

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