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

Will, A. J., Cova, G., Osterwalder, M., Chan, W. L., Wittler, L., Brieske, N., et al. (2017). Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog). Nature Genetics, 49(10), 1539-1545. doi:10.1038/ng.3939.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-7887-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0000-7888-0
Genre: Journal Article

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 Creators:
Will , A. J.1, 2, Author
Cova, G.1, 2, Author
Osterwalder, M., Author
Chan, W. L.1, 2, Author              
Wittler, L.3, Author              
Brieske, N.2, Author              
Heinrich, V.4, Author              
de Villartay, J. P., Author
Vingron, M.4, Author              
Klopocki, E., Author
Visel, A., Author
Lupianez, D. G.1, 2, Author
Mundlos, S.1, 2, Author              
Affiliations:
1Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany, ou_persistent22              
2Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
3Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
4Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              

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Free keywords: Animals Base Sequence Bone Diseases, Developmental/*genetics DNA Copy Number Variations DNA-Binding Proteins/deficiency/genetics Enhancer Elements, Genetic/*genetics Foot Deformities, Congenital/genetics Gene Deletion Gene Dosage Gene Duplication Gene Expression Regulation, Developmental/*genetics Gene Knockout Techniques Genes, Reporter Hedgehog Proteins/deficiency/genetics/*physiology Mice Mice, Inbred C57BL Osteogenesis/*genetics Polydactyly/genetics Regulatory Sequences, Nucleic Acid Sequence Analysis, DNA Skull/abnormalities Transcription, Genetic
 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.

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Language(s): eng - English
 Dates: 2017-08-282017-10
 Publication Status: Published in print
 Pages: 7
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/ng.3939
ISSN: 1546-1718 (Electronic)1061-4036 (Print)
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Title: Nature Genetics
  Other : Nature Genet.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America, Inc.
Pages: - Volume / Issue: 49 (10) Sequence Number: - Start / End Page: 1539 - 1545 Identifier: ISSN: 1061-4036
CoNE: /journals/resource/954925598609