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Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog)

Item Type:Article
Title:Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog)
Creators Name:Will, A.J. and Cova, G. and Osterwalder, M. and Chan, W.L. and Wittler, L. and Brieske, N. and Heinrich, V. and de Villartay, J.P. and Vingron, M. and Klopocki, E. and Visel, A. and Lupiáñez, D.G. and Mundlos, S.
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.
Keywords:Base Sequence, Congenital Foot Deformities, DNA Copy Number Variations, DNA Sequence Analysis, DNA-Binding Proteins, Developmental Bone Diseases, Developmental Gene Expression Regulation, Gene Deletion, Gene Dosage, Gene Duplication, Gene Knockout Techniques, Genetic Enhancer Elements, Genetic Transcription, Hedgehog Proteins, Inbred C57BL Mice, Nucleic Acid Regulatory Sequences, Osteogenesis, Polydactyly, Reporter Genes, Skull, Animals, Mice
Source:Nature Genetics
ISSN:1061-4036
Publisher:Nature Publishing Group (U.S.A.)
Volume:49
Number:10
Page Range:1539-1545
Date:October 2017
Official Publication:https://doi.org/10.1038/ng.3939
PubMed:View item in PubMed

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