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

Autor: Will AJ; Max Planck Institute for Molecular Genetics, RG Development and Disease, Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany., Cova G; Max Planck Institute for Molecular Genetics, RG Development and Disease, Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany., Osterwalder M; MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California, USA., Chan WL; Max Planck Institute for Molecular Genetics, RG Development and Disease, Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany., Wittler L; Department of Developmental Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany., Brieske N; Max Planck Institute for Molecular Genetics, RG Development and Disease, Berlin, Germany., Heinrich V; Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany., de Villartay JP; Genome Dynamics in the Immune System Laboratory, INSERM, UMR 1163, Institut Imagine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France., Vingron M; Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany., Klopocki E; Institute of Human Genetics, Biocentre, Julius Maximilians University Würzburg, Würzburg, Germany., Visel A; MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, California, USA.; US Department of Energy Joint Genome Institute, Walnut Creek, California, USA.; School of Natural Sciences, University of California, Merced, California, USA., Lupiáñez DG; Max Planck Institute for Molecular Genetics, RG Development and Disease, Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany., Mundlos S; Max Planck Institute for Molecular Genetics, RG Development and Disease, Berlin, Germany.; Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2017 Oct; Vol. 49 (10), pp. 1539-1545. Date of Electronic Publication: 2017 Aug 28.
DOI: 10.1038/ng.3939
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: