Bioinformatics and Systems Biology graduate program, University of California San Diego, La Jolla, California, United States of America.
Department of Pediatrics, University of California San Diego, La Jolla, California, United States of America.
PLoS Genet. 2021 May 13;17(5):e1009531. doi: 10.1371/journal.pgen.1009531. eCollection 2021 May.
Glucocorticoids are key regulators of glucose homeostasis and pancreatic islet function, but the gene regulatory programs driving responses to glucocorticoid signaling in islets and the contribution of these programs to diabetes risk are unknown. In this study we used ATAC-seq and RNA-seq to map chromatin accessibility and gene expression from eleven primary human islet samples cultured in vitro with the glucocorticoid dexamethasone at multiple doses and durations. We identified thousands of accessible chromatin sites and genes with significant changes in activity in response to glucocorticoids. Chromatin sites up-regulated in glucocorticoid signaling were prominently enriched for glucocorticoid receptor binding sites and up-regulated genes were enriched for ion transport and lipid metabolism, whereas down-regulated chromatin sites and genes were enriched for inflammatory, stress response and proliferative processes. Genetic variants associated with glucose levels and T2D risk were enriched in glucocorticoid-responsive chromatin sites, including fine-mapped variants at 51 known signals. Among fine-mapped variants in glucocorticoid-responsive chromatin, a likely casual variant at the 2p21 locus had glucocorticoid-dependent allelic effects on beta cell enhancer activity and affected SIX2 and SIX3 expression. Our results provide a comprehensive map of islet regulatory programs in response to glucocorticoids through which we uncover a role for islet glucocorticoid signaling in mediating genetic risk of T2D.
糖皮质激素是葡萄糖稳态和胰岛功能的关键调节剂，但驱动胰岛对糖皮质激素信号反应的基因调控程序以及这些程序对糖尿病风险的贡献尚不清楚。在这项研究中，我们使用 ATAC-seq 和 RNA-seq 从 11 个人类原代胰岛样本中进行了图谱绘制，这些样本在体外经过不同剂量和时间的糖皮质激素地塞米松培养。我们鉴定了数千个对糖皮质激素有显著活性变化的可及染色质位点和基因。在糖皮质激素信号转导中上调的染色质位点明显富含糖皮质激素受体结合位点，而上调的基因富含离子转运和脂质代谢，而下调的染色质位点和基因富含炎症、应激反应和增殖过程。与葡萄糖水平和 T2D 风险相关的遗传变异在糖皮质激素反应性染色质位点中富集，包括 51 个已知信号的精细映射变异。在糖皮质激素反应性染色质的精细映射变异中，2p21 基因座上的一个可能的因果变异在β细胞增强子活性上具有糖皮质激素依赖性等位基因效应，并影响 SIX2 和 SIX3 的表达。我们的研究结果提供了一个全面的胰岛对糖皮质激素反应的调控程序图谱，通过该图谱我们揭示了胰岛糖皮质激素信号在介导 T2D 的遗传风险中的作用。
