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| Status |
Public on Dec 31, 2023 |
| Title |
Super-enhancers require enhancers and facilitators to fully activate gene expression [ChIP-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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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| Overall design |
Characterisation of a mouse model lacking four out of the five alpha-globin super-enhancer constituents demonstrates that super-enhancer constituents rely on each other to achieve maximal target gene activation. Furthermore, the strongest alpha-globin super-enhancer constituent requires the other four constituents (or a subset thereof) for maximal enhancer-promoter interaction frequency, coactivator recruitment and eRNA expression. Rebuilding the alpha-globin super-enhancer further demonstrates the cooperation between its constituents. The super-enhancer is made up of two functionally distinct element types: active enhancers, and facilitators. Facilitators have little or no ability to activate gene expression directly, but they potentiate the activity of enhancers within the same cluster.
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| Contributor(s) |
Blayney J, Stolper R |
| Citation(s) |
38101409 |
| |
| Submission date |
Dec 07, 2022 |
| Last update date |
Feb 26, 2024 |
| Contact name |
Mira Kassouf |
| E-mail(s) |
mira.kassouf@imm.ox.ac.uk
|
| Organization name |
Weatherall Institute of Molecular Medicine
|
| Lab |
Doug Higgs
|
| Street address |
John Radcliffe Hospital
|
| City |
Oxford |
| State/province |
Oxfordshire |
| ZIP/Postal code |
OX3 9DS |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (46)
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| This SubSeries is part of SuperSeries: |
| GSE220463 |
Super-enhancers require enhancers and facilitators to fully activate gene expression |
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| Relations |
| BioProject |
PRJNA909806 |
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