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.; Heinrich, V.; de Villartay, J. P.; Vingron, M.; Klopocki, E.; Visel, A.; Lupianez, D. G.; Mundlos, S.

doi:10.1038/ng.3939

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

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Will , A. J.
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Cova, G.
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Chan, W. L.
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Wittler, L.
Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Brieske, N.
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Heinrich, V.
Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Vingron, M.
Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

Lupianez, D. G.
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mundlos, S.
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany;
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0000-7887-1

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.