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Preformed chromatin topology assists transcriptional robustness of Shh during limb development

Item Type:Article
Title:Preformed chromatin topology assists transcriptional robustness of Shh during limb development
Creators Name:Paliou, C. and Guckelberger, P. and Schöpflin, R. and Heinrich, V. and Esposito, A. and Chiariello, A.M. and Bianco, S. and Annunziatella, C. and Helmuth, J. and Haas, S. and Jerković, I. and Brieske, N. and Wittler, L. and Timmermann, B. and Nicodemi, M. and Vingron, M. and Mundlos, S. and Andrey, G.
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.
Keywords:Genetics, 3D Genome, Gene Regulation, Development, Limb, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:12390-12399
Date:18 June 2019
Official Publication:https://doi.org/10.1073/pnas.1900672116
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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