Enhancer loops appear stable during development and are associated with paused polymerase
Open accessAbstract
Developmental enhancers initiate transcription and are fundamental to our understanding of developmental networks, evolution and disease. Despite their importance, the properties governing enhancer-promoter interactions and their dynamics during embryogenesis remain unclear. At the β-globin locus, enhancer-promoter interactions appear dynamic and cell-type specific, whereas at the HoxD locus they are stable and ubiquitous, being present in tissues where the target genes are not expressed. The extent to which preformed enhancer-promoter conformations exist at other, more typical, loci and how transcription is eventually triggered is unclear. Here we generated a high-resolution map of enhancer three-dimensional contacts during Drosophila embryogenesis, covering two developmental stages and tissue contexts, at unprecedented resolution. Although local regulatory interactions are common, long-range interactions are highly prevalent within the compact Drosophila genome. Each enhancer contacts multiple enhancers, and promoters with similar expression, suggesting a role in their co-regulation. Notably, most interactions appear unchanged between tissue context and across development, arising before gene activation, and are frequently associated with paused RNA polymerase. Our results indicate that the general topology governing enhancer contacts is conserved from flies to humans and suggest that transcription initiates from preformed enhancer-promoter loops through release of paused polymerase.
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Such enhancer or repressor loop stability has been described during development where they are associated with paused polymerase and in human fibroblasts where TNF-α-responsive enhancers contact their target promoters before TNF-α activation.
“Such enhancer or repressor loop stability has been described during development where they are associated with paused polymerase28 and in human fibroblasts where TNF-α-responsive enhancers contact their target promoters before TNF-α activation29.”
From TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation (2015) · cites this paper as [28]
Proximity is sometimes maintained even when the gene or enhancer is inactive.
“On the other hand, proximity is sometimes maintained even when the gene or enhancer is inactive112,153.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [112]
Many enhancers are spatially proximate to their target promoter in 3D, but exceptions have been described.
“Many enhancers are spatially proximate to their target promoter in 3D109,110, but exceptions have been described111-114.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [112]
In Drosophila, pronounced changes in enhancer activity during embryonic development seem to occur without prominent changes in their 3D conformation.
“In Drosophila, pronounced changes in enhancer activity during embryonic development seem to occur without prominent changes in their 3D conformation [392, 393].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [392]
Many functional enhancers likely do not come into direct contact with their target promoters upon Drosophila development.
“Finally, multiple lines of recent evidence suggest that many functional enhancers likely do not come into direct contact with their target promoters upon Drosophila development (although some “permissive” enhancer–promoter loops are detectable as discussed above) [392].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [392]
In Drosophila melanogaster embryos, many developmental enhancers establish spatial contacts with their target promoters prior to the beginning of transcription from these promoters.
“Consistently, in Drosophila melanogaster embryos, many developmental enhancers establish spatial contacts with their target promoters prior to the beginning of transcription from these promoters [126].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [126]
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- Authors
- Ghavi-Helm, Y., Klein, F. A., Pakozdi, T., Ciglar, L., Noordermeer, D., Huber, W., & Furlong, E. E. M.
- Affiliations
- European Molecular Biology Laboratory (DE)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Furlong, Eileen E. M.
- Venue
- Nature
- Published
- 2014-07-02
- Volume
- 512
- Issue
- 7512
- Pages
- 96-100
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2008227324
- Cited by
- 536
- References
- 56
- Citations by year
- 2026: 22 · 2025: 27 · 2024: 35 · 2023: 34 · 2022: 56 · 2021: 44 · 2020: 41 · 2019: 49 · 2018: 51 · 2017: 56 · 2016: 59 · 2015: 50 · 2014: 11
- FWCI
- 23.92
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-07-13)
- Open access
- green
- infoscience.epfl.ch
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- enhancer-promoter interactions, 3D genome organization, Drosophila embryogenesis, developmental enhancers, cis-regulatory motifs, transcription initiation, chromatin looping, cis-regulatory networks, cis-regulatory evolution
- MeSH terms
- Animals, Binding Sites, Drosophila melanogaster, Enhancer Elements, Genetic, Humans, Promoter Regions, Genetic, DNA-Directed RNA Polymerases, Transcriptional Activation, Gene Expression Regulation, Developmental, Embryonic Development, Genome, Insect, Genetic Loci, Chromosomes, Insect, Transcription Initiation, Genetic
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