Endocrine Regulatory Genomics Laboratory, Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain.
Center for Diabetes Research and Welbio, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
Nat Genet. 2019 Nov;51(11):1588-1595. doi: 10.1038/s41588-019-0524-6. Epub 2019 Nov 1.
The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the β-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the β-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells. Our study illustrates how β cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.
1 型糖尿病（T1D）的早期阶段以局部自身免疫炎症和胰岛素产生的胰腺β细胞进行性丧失为特征。在这里，我们表明，暴露于促炎细胞因子会揭示β细胞调控景观的显著可塑性。我们通过绘制与β细胞转录组、蛋白质组和三维染色质结构变化相关的刺激反应增强子，扩展了人类胰岛调控元件的 repertoire。我们的数据表明，β细胞对细胞因子的反应是通过诱导新的调控区域以及激活由胰岛特异性转录因子预先结合的有潜力的调控元件来介导的。我们发现，T1D 相关基因座富含新映射的顺式调控区域，并确定 T1D 相关变异破坏了人类β细胞中细胞因子反应性增强子的活性。我们的研究说明了β细胞如何对促炎环境做出反应，并暗示了刺激反应胰岛增强子在 T1D 中的作用。
