A model of active transcription hubs that unifies the roles of active promoters and enhancers
Open accessAbstract
An essential questions of gene regulation is how large number of enhancers and promoters organize into gene regulatory loops. Using transcription-factor binding enrichment as an indicator of enhancer strength, we identified a portion of H3K27ac peaks as potentially strong enhancers and found a universal pattern of promoter and enhancer distribution: At actively transcribed regions of length of ∼200–300 kb, the numbers of active promoters and enhancers are inversely related. Enhancer clusters are associated with isolated active promoters, regardless of the gene's cell-type specificity. As the number of nearby active promoters increases, the number of enhancers decreases. At regions where multiple active genes are closely located, there are few distant enhancers. With Hi-C analysis, we demonstrate that the interactions among the regulatory elements (active promoters and enhancers) occur predominantly in clusters and multiway among linearly close elements and the distance between adjacent elements shows a preference of ∼30 kb. We propose a simple rule of spatial organization of active promoters and enhancers: Gene transcriptions and regulations mainly occur at local active transcription hubs contributed dynamically by multiple elements from linearly close enhancers and/or active promoters. The hub model can be represented with a flower-shaped structure and implies an enhancer-like role of active promoters.
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Recent evidence suggests that some promoter-promoter contacts likely have a direct cis-regulatory role similarly to enhancer-promoter contacts.
“recent evidence that promoter-promoter contacts within nested stripe domains preferentially involve transcriptionally active, rather than inactive, promoters [276], as well as the existence of epromoters (discussed above), suggest that some promoter-promoter contacts likely have a direct cis-regulatory role similarly to enhancer–promoter contacts.”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [493]
The paper’s ‘Validation of the model with Hi-C data’ section reports promoter–promoter interactions in active gene clusters and proposes that nearby active promoters might act as enhancers for one another. That supports the suggested cis-regulatory role, but our copy does not establish the cited sentence’s more specific claim about contacts within nested stripe domains preferentially involving active rather than inactive promoters. (LLM, conf=0.86)
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Cites
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Transcriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81 · see citing works
- Authors
- Zhu, I., Song, W., Ovcharenko, I., & Landsman, D.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Zhu, Iris
- Landsman, David
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-04-19
- Volume
- 49
- Issue
- 8
- Pages
- 4493-4505
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC8096258
- OpenAlex
- W3156071777
- Cited by
- 55
- References
- 16
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 19 · 2023: 8 · 2022: 6 · 2021: 5
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- public-domain
- Locations
- Nucleic Acids Research (publishedVersion, public-domain)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- enhancers, H3K27ac, 3D genome organization, chromatin interactions, Hi-C, enhancer clusters, gene expression regulation
- MeSH terms
- Chromatin Immunoprecipitation Sequencing, RNA-Seq, Acetylation, Chromosomes, Enhancer Elements, Genetic, Gene Expression Regulation, Multigene Family, Murine hepatitis virus, Histones, Humans, Models, Genetic, Promoter Regions, Genetic, Transcriptional Activation, Genome, Human, Databases, Genetic
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