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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 noncoding sequences and putative enhancers, but how these rearrangements induce disease is poorly understood. Here we investigate CNVs involving the regulatory landscape of IHH (encoding Indian hedgehog), which cause multiple, highly localized phenotypes including craniosynostosis and synpolydactyly. We show through transgenic reporter and genome-editing studies in mice that Ihh is regulated by a constellation of at least nine enhancers with individual tissue specificities in the digit anlagen, growth plates, skull sutures and fingertips. Consecutive deletions, resulting in growth defects of the skull and long bones, showed that these enhancers function in an additive manner. Duplications, in contrast, caused not only dose-dependent upregulation but also misexpression of Ihh, leading to abnormal phalanges, fusion of sutures and syndactyly. Thus, precise spatiotemporal control of developmental gene expression is achieved by complex multipartite enhancer ensembles. Alterations in the composition of such clusters can result in gene misexpression and disease.

journal_name

Nat Genet

journal_title

Nature genetics

authors

Will AJ,Cova G,Osterwalder M,Chan WL,Wittler L,Brieske N,Heinrich V,de Villartay JP,Vingron M,Klopocki E,Visel A,Lupiáñez DG,Mundlos S

doi

10.1038/ng.3939

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

1539-1545

issue

10

eissn

1061-4036

issn

1546-1718

pii

ng.3939

journal_volume

49

pub_type

杂志文章

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