Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk
Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk
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DOI：
10.1038/s41467-019-09975-4
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发表时间：
2019-05-07
影响因子：
16.6
通讯作者：
Gaulton, Kyle J.
中科院分区：
文献类型：
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作者：
Greenwald, William W.;Chiou, Joshua;Gaulton, Kyle J.
影响胰岛增强子的遗传变异是T2 D风险的核心，但胰岛增强子活性的基因靶点在很大程度上是未知的。我们在三个胰岛样本中使用Hi-C检测生成胰岛染色质环的高分辨率图，并使用环来注释使用ATAC-seq和已发表的ChIP-seq数据定义的胰岛增强子的靶基因。我们确定了数千个胰岛增强子的候选靶基因，发现增强子环与胰岛特异性基因表达相关。我们对影响胰岛增强子的T2 D风险变体进行了精细定位，发现使用染色质环和eQTL定位定义的这些变体的候选靶基因在蛋白质转运和分泌途径中富集。在IGF 2BP 2处，精细定位的T2 D变体降低胰岛增强子活性和IGF 2BP 2表达，并且小鼠胰岛中IGF 2BP 2的条件性失活损害葡萄糖刺激的胰岛素分泌。我们的研究结果为研究胰岛增强子功能和识别参与T2 D风险的基因提供了资源。
Genetic variants affecting pancreatic islet enhancers are central to T2D risk, but the gene targets of islet enhancer activity are largely unknown. We generate a high-resolution map of islet chromatin loops using Hi-C assays in three islet samples and use loops to annotate target genes of islet enhancers defined using ATAC-seq and published ChIP-seq data. We identify candidate target genes for thousands of islet enhancers, and find that enhancer looping is correlated with islet-specific gene expression. We fine-map T2D risk variants affecting islet enhancers, and find that candidate target genes of these variants defined using chromatin looping and eQTL mapping are enriched in protein transport and secretion pathways. At IGF2BP2, a fine-mapped T2D variant reduces islet enhancer activity and IGF2BP2 expression, and conditional inactivation of IGF2BP2 in mouse islets impairs glucose-stimulated insulin secretion. Our findings provide a resource for studying islet enhancer function and identifying genes involved in T2D risk.