文章基本信息

标题：Preformed chromatin topology assists transcriptional robustness of Shh during limb development
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作者：Christina Paliou ; Christina Paliou ; Philine Guckelberger 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2019
卷号：116
期号：25
页码：12390-12399
DOI：10.1073/pnas.1900672116
出版社：The National Academy of Sciences of the United States of America
摘要：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.
关键词：genetics ; 3D genome ; gene regulation ; development ; limb