The Conserved Sonic Hedgehog Limb Enhancer Consists of Discrete Functional Elements that Regulate Precise Spatial Expression
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Expression of sonic hedgehog (Shh) in the limb bud is regulated by an enhancer called the zone of polarizing activity regulatory sequence (ZRS), which, in evolution, belongs to an ancient group of highly conserved cis regulators found in all classes of vertebrates. Here, we examined the endogenous ZRS in mice, using genome editing to establish the relationship between enhancer composition and embryonic phenotype. We show that enhancer activity is a consolidation of distinct activity domains. Spatial restriction of Shh expression is mediated by a discrete repressor module, whereas levels of gene expression are controlled by large overlapping domains containing varying numbers of HOXD binding sites. The number of HOXD binding sites regulates expression levels incrementally. Substantial portions of conserved sequence are dispensable, indicating the presence of sequence redundancy. We propose a collective model for enhancer activity in which function is an integration of discrete expression activities and redundant components that drive robust expression.
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Functional analysis of the ZRS enhancer revealed that these mutations either create gain-of-function binding sites for activating transcription factors ETS1 and GABPα, or abolish a repressive transcription factor site, leading to ectopic SHH expression.
“Functional analysis of the ZRS enhancer revealed that these mutations either create gain-of-function binding sites for activating TFs (ETS1 and GABPα) [199], or abolish a repressive TF site [200], leading to ectopic SHH expression.”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [200]
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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
- Lettice, L. A., Devenney, P., De Angelis, C., & Hill, R. E.
- Affiliations
- Institute of Genetics and Cancer (GB)
- Corresponding author
- Hill, Robert E.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 20
- Issue
- 6
- Pages
- 1396-1408
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5561167
- OpenAlex
- W2743316243
- Cited by
- 70
- References
- 4
- Citations by year
- 2026: 4 · 2025: 16 · 2024: 8 · 2023: 5 · 2022: 11 · 2021: 10 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 1
- FWCI
- 1.79
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Funders
- MRC
- 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, enhancer architecture, cis-regulatory elements, spatial gene expression, sequence redundancy, limb development
- MeSH terms
- Animals, Binding Sites, Enhancer Elements, Genetic, Extremities, Phenotype, Protein Binding, Conserved Sequence, Gene Expression Regulation, Developmental, Mice, Hedgehog Proteins
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