Will Anja J, Cova Giulia, Osterwalder Marco, Chan Wing-Lee, Wittler Lars, Brieske Norbert, Heinrich Verena, de Villartay Jean-Pierre, Vingron Martin, Klopocki Eva, Visel Axel, Lupiáñez Darío G, Mundlos Stefan
Max Planck Institute for Molecular Genetics, RG Development and Disease, Berlin, Germany.
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Nat Genet. 2017 Oct;49(10):1539-1545. doi: 10.1038/ng.3939. Epub 2017 Aug 28.
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.
拷贝数变异（CNV）通常包含非编码序列和假定的增强子，但这些重排如何引发疾病却鲜为人知。在此，我们研究涉及IHH（编码印度刺猬蛋白）调控格局的CNV，其会导致多种高度局部化的表型，包括颅缝早闭和并指多指畸形。我们通过对小鼠进行转基因报告基因和基因组编辑研究表明，Ihh受至少九个增强子的调控，这些增强子在指原基、生长板、颅骨缝线和指尖具有各自的组织特异性。连续缺失导致颅骨和长骨生长缺陷，表明这些增强子以累加方式发挥作用。相比之下，重复不仅导致Ihh剂量依赖性上调，还导致其错误表达，从而导致指骨异常、缝线融合和并指。因此，发育基因表达的精确时空控制是通过复杂的多部分增强子组合实现的。此类簇的组成改变会导致基因错误表达和疾病。
