Shh and ZRS enhancer colocalisation is specific to the zone of polarising activity
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Abstract
Limb-specific Shh expression is regulated by the (∼1 Mb distant) ZRS enhancer. In the mouse, limb bud-restricted spatiotemporal Shh expression occurs from ∼E10 to E11.5 at the distal posterior margin and is essential for correct autopod formation. Here, we have analysed the higher-order chromatin conformation of Shh in expressing and non-expressing tissues, both by fluorescence in situ hybridisation (FISH) and by chromosome conformation capture (5C). Conventional and super-resolution light microscopy identified significantly elevated frequencies of Shh/ZRS colocalisation only in the Shh-expressing regions of the limb bud, in a conformation consistent with enhancer-promoter loop formation. However, in all tissues and at all developmental stages analysed, Shh-ZRS spatial distances were still consistently shorter than those to a neural enhancer located between Shh and ZRS in the genome. 5C identified a topologically associating domain (TAD) over the Shh/ZRS genomic region and enriched interactions between Shh and ZRS throughout E11.5 embryos. Shh/ZRS colocalisation, therefore, correlates with the spatiotemporal domain of limb bud-specific Shh expression, but close Shh and ZRS proximity in the nucleus occurs regardless of whether the gene or enhancer is active. We suggest that this constrained chromatin configuration optimises the opportunity for the active enhancer to locate and instigate the expression of Shh.
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Active enhancers are often in physical proximity to the promoters they activate, regardless of the genomic distances between these enhancers and promoters.
“First, it was shown that active enhancers are often in physical proximity to the promoters they activate, regardless of the genomic distances between these enhancers and promoters [32,33,34].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [34]
The Introduction reports proximity between Shh and its distant ZRS enhancer, and the Results describe greater colocalisation where the enhancer is active. This supports the claim for a long-range enhancer–gene pair, but the paper does not establish that active enhancers are often close to their promoters regardless of genomic distance across enhancers generally. Page numbers are not provided in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredProximity 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 [153]
In most of the cases studied, the establishment of communication between the enhancer and the promoter correlates with a reduction in the distance between them, but this distance still remains significant (100-400 nm).
“In most of the cases studied, the establishment of communication between the enhancer and the promoter correlates with a reduction in the distance between them. However, this distance still remains significant (100–400 nm [34,101,102,103].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [34]
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- Authors
- Williamson, I., Lettice, L. A., Hill, R. E., & Bickmore, W. A.
- Affiliations
- Institute of Genetics and Cancer (GB)
- Corresponding author
- Hill, Robert E.
- Bickmore, Wendy A.
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2016-08-15
- Volume
- 143
- Issue
- 16
- Pages
- 2994-3001
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC5004883
- OpenAlex
- W2953029843
- Cited by
- 124
- References
- 35
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 9 · 2023: 8 · 2022: 14 · 2021: 18 · 2020: 14 · 2019: 17 · 2018: 13 · 2017: 14 · 2016: 4 · 2014: 1
- FWCI
- 8.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Development (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- 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 › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- Sonic hedgehog, limb bud, chromatin conformation, topologically associating domains, enhancer-promoter loops, limb development, gene expression regulation, mouse embryo
- MeSH terms
- Animals, Chromosomes, Enhancer Elements, Genetic, In Situ Hybridization, Fluorescence, Gene Expression Regulation, Developmental, Limb Buds, Mice, Hedgehog Proteins
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