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研究揭示促炎细胞因子对β细胞的表观影响
作者:小柯机器人 发布时间:2019/11/3 0:02:07

西班牙Germans Trias i Pujol大学医院与研究所的Lorenzo Pasquali团队揭示了促炎细胞因子对β细胞调节作用,并为1型糖尿病(T1D)的发病机制提供了新的见解。11月1日,《自然—遗传学》在线发表了这一成果。

研究人员发现,促炎细胞因子的接触揭示了β细胞调节表观图谱的显著可塑性。通过映射与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响应性增强子,研究人员扩展了人类胰岛调节元件的功能。这些数据表明,β细胞对细胞因子的反应是通过诱导新的调控区以及活化调控元件(被胰岛特异性转录因子预先结合)的激活来介导的。研究人员发现,与T1D相关的基因座富含新定位的顺式调控区域,并鉴定了可破坏人类β细胞中细胞因子响应型增强子活性的T1D相关变体。这项研究说明了β细胞如何对促炎环境做出反应,并暗示T1D中刺激响应胰岛增强子的作用。

据介绍,T1D早期阶段的特征是局部自身免疫炎症和胰岛素产生性胰腺β细胞的逐步丢失。

附:英文原文
 
Title:The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes
 
Author:Mireia Ramos-Rodríguez, Helena Raurell-Vila, Maikel L. Colli, Maria Inês Alvelos, Marc Subirana-Granés, Jonàs Juan-Mateu, Richard Norris, Jean-Valery Turatsinze, Ernesto S. Nakayasu, Bobbie-Jo M. Webb-Robertson, Jamie R. J. Inshaw, Piero Marchetti, Lorenzo Piemonti, Manel Esteller, John A. Todd, Thomas O. Metz, Décio L. Eizirik & Lorenzo Pasquali
 
Issue&Volume:01 November 2019
 
Abstract: 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.
 
DOI:10.1038/s41588-019-0524-6
 
Source: https://www.nature.com/articles/s41588-019-0524-6

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex