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Preformed chromatin topology assists transcriptional robustness of Shh during limb development

Paliou, Christina
Guckelberger, Philine
Schöpflin, Robert
Heinrich, Verena
Esposito, Andrea
Chiariello, Andrea M
Bianco, Simona
Annunziatella, Carlo
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Published in Proceedings of the National Academy of Sciences. 2019
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.
PMID: 31147463
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Article (Published version) (2.2 MB) - document accessible for UNIGE members only Limited access to UNIGE
Research group Contrôle épigénétique du développement embryonnaire (999)
Projects FNS: P00P3_176802
FNS: P300PA_160964
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PALIOU, Christina et al. Preformed chromatin topology assists transcriptional robustness of Shh during limb development. In: Proceedings of the National Academy of Sciences, 2019.

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Deposited on : 2019-06-26

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