2017
DOI: 10.1038/ng.3939
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Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog)

Abstract: Copy number variations (CNVs) often include non-coding sequence and putative enhancers but how these rearrangements induce disease is poorly understood. Here we investigate CNVs involving the regulatory landscape of Indian hedgehog (IHH), causing multiple, highly localised phenotypes including craniosynostosis and synpolydactyly1,2. We show through transgenic reporter and genome editing studies in mice that Ihh is regulated by a constellation of at least 9 enhancers with individual tissue specificities in the … Show more

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Cited by 115 publications
(126 citation statements)
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“…Studies of individual loci have identified examples of mammalian enhancers near the same gene with remarkably similar spatiotemporal activity patterns or functions 15,2732 , reminiscent of invertebrate “shadow enhancers” 8,9,3335 . The lack of dramatic morphological phenotypes in our enhancer deletion mouse models suggests that panels of mammalian enhancers with large degrees of redundancy act as a regulatory buffer for key developmental processes, thereby reducing the likelihood of severe consequences from genetic or environmental challenges 8 .…”
Section: Textmentioning
confidence: 99%
“…Studies of individual loci have identified examples of mammalian enhancers near the same gene with remarkably similar spatiotemporal activity patterns or functions 15,2732 , reminiscent of invertebrate “shadow enhancers” 8,9,3335 . The lack of dramatic morphological phenotypes in our enhancer deletion mouse models suggests that panels of mammalian enhancers with large degrees of redundancy act as a regulatory buffer for key developmental processes, thereby reducing the likelihood of severe consequences from genetic or environmental challenges 8 .…”
Section: Textmentioning
confidence: 99%
“…Figures 3A and B and The nine mouse enhancer data used for analyses displayed in Figure 3C and Suppl. Figure S11 were obtained from Will et al 37 (https://media.nature.com/original/natureassets/ng/journal/v49/n10/extref/ng.3939-S1.pdf, Supplementary Table S4). The mouse coordinates were mapped to human using CrossMap (v.0.2.5.…”
Section: External Datasets the Crispri Coordinates And Scores Used Fmentioning
confidence: 99%
“…Next, we chose a human disease that involves the rearrangement of the regulatory landscape of IHH (encoding Indian hedgehog), which cause developmental defects including craniosynostosis and synpolydactyly 35,36 . Will et al 37 identified nine enhancers with individual tissue specificities in the digit anlagen, growth plates, skull sutures and fingertips. The IHH region in humans shares a common structure with the mouse locus that was used for the model by Will et al 37 In their study, consecutive deletions resulted in growth defects of the skull and long bones that confirmed that the enhancers function in an additive manner.…”
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confidence: 99%
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“…This contrasts other loci, where robustness is mainly ensured via the additive effect of multiple, partially redundant enhancers. At the Hoxd and Ihh loci for example, several enhancers have been shown to globally contribute to the final transcription pattern(44)(45)(46)(47). At these loci, a preformed interaction may be unnecessary as a promoter samples the cumulative activities of all its enhancers, each of which possesses an overlapping and redundant activity.…”
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confidence: 99%