Decreased Enhancer-Promoter Proximity Accompanying Enhancer Activation
Open accessAbstract
Enhancers can regulate the promoters of their target genes over very large genomic distances. It is widely assumed that mechanisms of enhancer action involve the reorganization of three-dimensional chromatin architecture, but this is poorly understood. The predominant model involves physical enhancer-promoter interaction by looping out the intervening chromatin. However, studying the enhancer-driven activation of the Sonic hedgehog gene (Shh), we have identified a change in chromosome conformation that is incompatible with this simple looping model. Using super-resolution 3D-FISH and chromosome conformation capture, we observe a decreased spatial proximity between Shh and its enhancers during the differentiation of embryonic stem cells to neural progenitors. We show that this can be recapitulated by synthetic enhancer activation, is impeded by chromatin-bound proteins located between the enhancer and the promoter, and appears to involve the catalytic activity of poly (ADP-ribose) polymerase. Our data suggest that models of enhancer-promoter communication need to encompass chromatin conformations other than looping.
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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 [113]
Synthetic activation of the Shh promoter, bypassing the need for enhancer activation and causing increased transcription, did not lead to increased distance.
“Notably, synthetic activation of the Shh promoter, bypassing the need for enhancer activation and causing increased transcription, did not lead to increased distance [407].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [407]
Recruiting activators such as VP64, Mediator and SIX3 to this enhancer also increased the enhancer-promoter distance whilst upregulating Shh expression.
“Recruiting activators such as VP64, Mediator and SIX3 to this enhancer also increased the enhancer–promoter distance whilst upregulating Shh expression [407].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [407]
A proximal enhancer of the Shh gene moves further away from the Shh promoter upon activation, according to both 3C-derived methods and imaging.
“In contrast, a proximal enhancer of the Shh gene moves further away from the Shh promoter upon activation, according to both 3C-derived methods and imaging [407].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [407]
In some cases, the distance between the enhancer and the target promoter does not change upon transcription activation or even increases.
“In some cases, the distance between the enhancer and the target promoter does not change upon transcription activation [104] or even increases [89].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [89]
Activation of the Shh gene during neuronal differentiation of mouse embryonic stem cells is accompanied by a decrease in the spatial proximity between Shh and the SBE6 enhancer that controls its work.
“For example, activation of the Shh gene during neuronal differentiation of mouse embryonic stem cells is accompanied by a decrease in the spatial proximity between Shh and the SBE6 enhancer that controls its work [89].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [89]
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Cites
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Self-citation<i>Shh</i> and ZRS enhancer colocalisation is specific to the zone of polarising activity
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- Authors
- Benabdallah, N. S., Williamson, I., Illingworth, R. S., Kane, L., Boyle, S., Sengupta, D., Grimes, G. R., Therizols, P., & Bickmore, W. A.
- Affiliations
- Institute of Genetics and Cancer (GB)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Bickmore, Wendy A.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 76
- Issue
- 3
- Pages
- 473-484.e7
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6838673
- OpenAlex
- W2971821708
- Cited by
- 335
- References
- 10
- Citations by year
- 2026: 23 · 2025: 59 · 2024: 56 · 2023: 40 · 2022: 48 · 2021: 58 · 2020: 44 · 2019: 7
- FWCI
- 12.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- Medical Research Council
- 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 › Epigenetics and DNA Methylation
- Keywords
- enhancer-promoter interactions, Sonic hedgehog, 3D genome organization, chromatin looping, poly(ADP-ribose) polymerase, chromatin-bound proteins, neural progenitor differentiation, embryonic stem cells, enhancer activation, chromosome conformation capture
- MeSH terms
- Mouse Embryonic Stem Cells, Poly (ADP-Ribose) Polymerase-1, Animals, Cell Line, Enhancer Elements, Genetic, Models, Genetic, Neurons, Nucleic Acid Conformation, Promoter Regions, Genetic, Transcriptional Activation, Gene Expression Regulation, Developmental, Chromatin Assembly and Disassembly, Mice, Hedgehog Proteins, Neurogenesis, SOXB1 Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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