Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes
Human pancreatic islet three-dimensional chromatin architecture provides insights into the genetics of type 2 diabetes
复制标题
人类胰岛三维染色质构筑为2型糖尿病的遗传学研究提供了线索
DOI：
10.1038/s41588-019-0457-0
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发表时间：
2019-07-01
期刊：
影响因子：
30.8
通讯作者：
Ferrer, Jorge
中科院分区：
文献类型：
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作者：
Miguel-Escalada, Irene;Bonas-Guarch, Silvia;Ferrer, Jorge
遗传学研究有望深入了解2型糖尿病（T2D）的分子机制。与T2D相关的变异通常位于组织特异性增强子簇或超级增强子中。到目前为止，这些结构域是通过线性基因组图谱中的增强子聚类来定义的，而不是在三维空间中。此外，它们的靶基因往往是未知的。我们已经在人类胰岛中创建了启动子捕获的Hi-C图谱。这将与糖尿病相关的增强子与目标基因联系起来，这些基因通常位于数百个碱基之外。该研究还发现，形成3D枢纽的胰岛增强子、超级增强子和活性促进子有大约1300组，其中一些显示出协调的葡萄糖依赖活性。我们证明了枢纽的遗传变异会影响胰岛素分泌的遗传性，并表明枢纽注释可以用于多基因评分，预测由胰岛调节变异驱动的T2D风险。因此，人类胰岛三维染色质结构为解释T2D全基因组关联研究（GWAS）信号提供了一个框架。
Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer clusters or super-enhancers. So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in three-dimensional (3D) space. Furthermore, their target genes are often unknown. We have created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers to their target genes, often located hundreds of kilobases away. It also revealed >1,300 groups of islet enhancers, super-enhancers and active promoters that form 3D hubs, some of which show coordinated glucose-dependent activity. We demonstrate that genetic variation in hubs impacts insulin secretion heritability, and show that hub annotations can be used for polygenic scores that predict T2D risk driven by islet regulatory variants. Human islet 3D chromatin architecture, therefore, provides a framework for interpretation of T2D genome-wide association study (GWAS) signals.