Preformed chromatin topology assists transcriptional robustness of Shh during limb development
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Abstract
Long-range gene regulation involves physical proximity between enhancers and promoters to generate precise patterns of gene expression in space and time. However, in some cases, proximity coincides with gene activation, whereas, in others, preformed topologies already exist before activation. In this study, we investigate the preformed configuration underlying the regulation of the Shh gene by its unique limb enhancer, the ZRS , in vivo during mouse development. Abrogating the constitutive transcription covering the ZRS region led to a shift within the Shh–ZRS contacts and a moderate reduction in Shh transcription. Deletion of the CTCF binding sites around the ZRS resulted in the loss of the Shh–ZRS preformed interaction and a 50% decrease in Shh expression but no phenotype, suggesting an additional, CTCF-independent mechanism of promoter–enhancer communication. This residual activity, however, was diminished by combining the loss of CTCF binding with a hypomorphic ZRS allele, resulting in severe Shh loss of function and digit agenesis. Our results indicate that the preformed chromatin structure of the Shh locus is sustained by multiple components and acts to reinforce enhancer–promoter communication for robust transcription.
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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 [451]
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- Authors
- Paliou, C., Guckelberger, P., Schöpflin, R., Heinrich, V., Esposito, A., Chiariello, A. M., Bianco, S., Annunziatella, C., Helmuth, J., Haas, S., Jerković, I., Brieske, N., Wittler, L., Timmermann, B., Nicodemi, M., Vingron, M., Mundlos, S., & Andrey, G.
- Affiliations
- Berlin-Brandenburger Centrum für Regenerative Therapien (DE)
- Max Planck Institute for Molecular Genetics (DE)
- Istituto Nazionale di Fisica Nucleare (IT)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-05-30
- Volume
- 116
- Issue
- 25
- Pages
- 12390-12399
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6589666
- OpenAlex
- W2950463539
- Cited by
- 163
- References
- 20
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 22 · 2023: 23 · 2022: 25 · 2021: 35 · 2020: 22 · 2019: 11 · 2012: 1
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- HAL (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (SP1532/2-1, MU 880/14)
- Max-Planck-Gesellschaft (Mundlos)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (PP00P3_176802, P300PA_160964)
- HHS | National Institutes of Health (1U54DK107977-01)
- 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 › Developmental Biology › Congenital limb and hand anomalies
- Keywords
- Sonic hedgehog, limb development, enhancer-promoter interactions, CTCF binding sites, long-range gene regulation, mouse embryo
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Animals, Binding Sites, Chromatin, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Extremities, Membrane Proteins, Promoter Regions, Genetic, Transcription, Genetic, Down-Regulation, Cell Cycle Proteins, Mice, Hedgehog Proteins
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