Developmentally regulated Shh expression is robust to TAD perturbations
Open accessPreprint — published as 10.1242/dev.179523
Abstract
Topologically Associating Domains (TADs) have been proposed to both guide and constrain enhancer activity. Shh is located within a TAD known to contain all its enhancers. To investigate the importance of chromatin conformation and TAD integrity on developmental gene regulation, we have manipulated the Shh TAD – creating internal deletions, deleting CTCF sites including those at TAD boundaries, as well as larger deletions and inversions of TAD boundaries. Chromosome conformation capture and fluorescence in situ hybridisation assays were used the investigate changes in chromatin conformation that result from these manipulations. Our data suggest that the substantial alteration of TAD structure has no readily detectable effect on Shh expression patterns during development – except where enhancers are deleted - and results in no detectable phenotypes. Only in the case of a larger deletion of one TAD boundary could some ectopic influence of the Shh limb enhancer be detected on a gene - Mnx1 in the neighbouring TAD. Our data suggests that, contrary to expectations, the developmental regulation of Shh expression is remarkably robust to TAD perturbations.
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Targeted deletions of TAD boundary-forming CTCF sites in the Shh locus did not entirely disrupt developmental regulation of Shh expression.
“targeted deletions of TAD boundary-forming CTCF sites in the Shh locus did not entirely disrupt the developmental regulation of Shh expression [450, 451].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [450]
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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
- Williamson, I., Kane, L., Devenney, P. S., Anderson, E., Kilanowski, F., Hill, R. E., Bickmore, W. A., & Lettice, L. A.
- Affiliations
- Institute of Genetics and Cancer (GB)
- Corresponding author
- Bickmore, Wendy A.
- Lettice, Laura A.
- Venue
- Development
- Publisher
- openRxiv
- Published
- 2019-04-15
- Volume
- 146
- Issue
- 19
- ISSN
- 0950-1991 (ISSN-L)
- PMC
- PMC7212092
- OpenAlex
- W2973219761
- Cited by
- 138
- References
- 1
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 15 · 2023: 17 · 2022: 18 · 2021: 40 · 2020: 21 · 2019: 12
- FWCI
- 7.53
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Development (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Darwin Trust of Edinburgh
- Medical Research Council (MC_UU_00007/8, MC_UU_00007/2)
- 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, topologically associating domains, chromatin conformation, enhancer regulation, CTCF, MNX1, developmental gene regulation, 3D genome organization
- MeSH terms
- CCCTC-Binding Factor, Animals, Chromatin, Embryo, Mammalian, Enhancer Elements, Genetic, Extremities, Organ Specificity, Phenotype, Genome, Sequence Deletion, Gene Expression Regulation, Developmental, Base Pairing, Mice, Hedgehog Proteins
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