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Transcriptional super-enhancers connected to cell identity and disease

ABSTRACT: Super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that control and define cell identity. Improved understanding of the roles super-enhancers play in biology would be afforded by knowing the constellation of factors that constitute these domains and by identifying super-enhancers across the spectrum of human cell types. We describe here the population of transcription factors, cofactors, chromatin regulators and core transcription apparatus that occupy super-enhancers in embryonic stem cells (ESCs) and evidence that super-enhancers are highly transcribed. We then use epigenomic data to produce a catalogue of super-enhancers in a broad range of human cell types. These super-enhancer domains are associated with genes encoding master transcription factors and other components that play important roles in the biology of these cells. Interestingly, sequence variation associated with a broad spectrum of diseases is especially enriched in the super-enhancers of disease-relevant cell types. Furthermore, we find that cancer cells generate super-enhancers at oncogenes and other genes that play important roles in tumor pathogenesis. We discuss these insights and their implications for future study of human health and disease.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE51522 | GEO | 2013/10/23

SECONDARY ACCESSION(S): PRJNA223352

REPOSITORIES: GEO

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Transcriptional super-enhancers connected to cell identity and disease

Project description:Super-enhancers are large clusters of transcriptional enhancers that drive expression of genes that control and define cell identity. Improved understanding of the roles super-enhancers play in biology would be afforded by knowing the constellation of factors that constitute these domains and by identifying super-enhancers across the spectrum of human cell types. We describe here the population of transcription factors, cofactors, chromatin regulators and core transcription apparatus that occupy super-enhancers in embryonic stem cells (ESCs) and evidence that super-enhancers are highly transcribed. We then use epigenomic data to produce a catalogue of super-enhancers in a broad range of human cell types. These super-enhancer domains are associated with genes encoding master transcription factors and other components that play important roles in the biology of these cells. Interestingly, sequence variation associated with a broad spectrum of diseases is especially enriched in the super-enhancers of disease-relevant cell types. Furthermore, we find that cancer cells generate super-enhancers at oncogenes and other genes that play important roles in tumor pathogenesis. We discuss these insights and their implications for future study of human health and disease. ChIP-Seq for transcription factors in mouse embryonic stem cells and H3K27ac in Jurkat T-ALL cell line RNA-Seq for mouse embryonic stem cells

2013-10-23 | E-GEOD-51522 | biostudies-arrayexpress

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

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

Low RNA stability signifies increased post-transcriptional regulation of cell identity genes

Project description:Cell identity genes are distinct from other genes with respect to the epigenetic mechanisms to activate their transcription, e.g., by super-enhancers and Broad H3K4me3 domains. However, it remains unclear whether their post-transcriptional regulation is also unique. We performed a systematic analysis of transcriptome-wide RNA stability in nine cell types and found that unstable transcripts were enriched in cell identity-related pathways while stable transcripts were enriched in housekeeping pathways. Joint analyses of RNA stability and chromatin state revealed that significant enrichment of super-enhancers and broad H3K4me3 domains at the gene loci of unstable transcripts. Intriguingly, the RNA m6A methyltransferase, METTL3, preferentially binds to chromatin at super-enhancers, broad H3K4me3 domains, and their associated genes. METTL3 binding intensity is positively correlated with RNA m6A methylation and negatively correlated with RNA stability of cell identity genes, likely due to co-transcriptional m6A modifications promoting RNA decay. Nanopore direct RNA-seq showed that METTL3 knockdown has a stronger effect on RNA m6A and mRNA stability for cell identity genes. Our data suggest a run and brake model, where cell identity genes undergo both frequent transcription and fast RNA decay to achieve precise regulation of RNA expression.

2023-03-31 | GSE185990 | GEO

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

Super-enhancers require enhancers and facilitators to fully activate gene expression [ChIP-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 | GSE220456 | GEO

Super-enhancers require enhancers and facilitators to fully activate gene expression [Tiled-C]

2023-12-31 | GSE219077 | GEO

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

2023-12-31 | GSE219062 | GEO

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

2023-12-31 | GSE219056 | GEO

NOTCH1/RBPJ complexes drive target gene expression through dynamic interactions with super-enhancers

Project description:The main oncogenic driver in T-lymphoblastic leukemia (T-LL) is NOTCH1, which activates genes by forming chromatin-associated Notch transcription complexes. Gamma-secretase (GSI) inhibitor treatment prevents NOTCH1 nuclear localization, but most genes with NOTCH1 binding sites are insensitive to GSI. Here, we demonstrate that fewer than 10% of NOTCH1 binding sites show dynamic changes in NOTCH1 occupancy when T-LL cells are toggled between the Notch-on and –off states with GSI. Dynamic NOTCH1 sites are functional, being highly associated with Notch target genes, are located mainly in distal enhancers, and frequently overlap with RUNX1 binding. In line with the latter association, we show that expression of IL7R, a gene with key roles in normal T cell development and in T-LL, is coordinately regulated by Runx factors and dynamic NOTCH1 binding to distal enhancers. Like IL7R, most Notch target genes and associated dynamic NOTCH1 binding sites co-occupy chromatin domains defined by constitutive binding of CCCTC binding factor (CTCF), which appears to restrict the regulatory potential of dynamic NOTCH1 sites. More remarkably, the majority of dynamic NOTCH1 sites lie in super-enhancers, distal elements with exceptionally broad and high levels of H3K27ac. Changes in Notch occupancy produces dynamic alterations in H3K27ac levels across the entire breadth of super-enhancers and in the promoters of nearby Notch target genes. These findings link regulation of super-enhancer function to NOTCH1, a master regulatory factor and potent oncoprotein in the context of immature T cells, and delineate a generally applicable roadmap for identifying functional Notch sites in cellular genomes. NOTCH1/RBPJ complexes binding dynamics in human T-LL

2013-12-27 | E-GEOD-51800 | biostudies-arrayexpress

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