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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE219056 | GEO | 2023/12/31

REPOSITORIES: GEO

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

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.

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

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

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Chromatin interactions involving super-enhancers associate with specific expression patterns of target genes

Project description:Super-enhancers may regulate target genes through chromatin looping. We connected super-enhancers in the K562 chronic myelogenous leukemia cell line with chromatin interactions identified from Chromatin Interaction Analysis with Paired-End Tag (ChIA-PET) data. Gene expression at proximal elements that are connected with distal super-enhancers showed significantly higher cell-type specificity than at proximal elements connected with other elements or not involved in interaction. 4C and Episwitch analysis of chromatin interactions showed that certain chromatin interactions are cell-specific, but others are more general. While super-enhancers upstream of c-MYC at the MYC-335 element can be found in other cancers, only super-enhancers downstream of c-MYC can be found in K562. 4C analysis of the c-MYC promoter revealed no chromatin interactions that are directed upstream of c-MYC, but only downstream of c-MYC, in the PVT1 long non-coding RNA gene. Cell-specific usage of super-enhancers could explain why the MYC-335 element that is associated with many solid cancers such as colorectal cancer and breast cancer, but not with leukemia. Surprisingly, we found that a chromatin interaction between c-MYC and a c-MYC super-enhancer is lost in chronic myelogenous leukemia patient blood as compared with blood from individuals without the disease through Oxford Biodynamicsâ?? Episwitch analysis. These results provide evidence for fine-tuning of expression patterns, such as cell-specific regulation of target genes by distal super-enhancers through chromatin interactions and an association between chromatin interactions and disease, and highlight that super-enhancers are more complex than previously described. Examination of several chromatin interactions involving super-enhancers using 4C-Seq and Episwitch (TM)

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