美国杰克逊基因组医学实验室Michael L. Stitzel和Duygu Ucar共同合作，近期取得重要工作进展。他们通过研究多组学人类胰岛内质网和细胞因子应激反应图谱，为2型糖尿病提供遗传学见解。相关研究成果2024年10月8日在线发表于《细胞—代谢》杂志上。

据介绍，内质网（ER）和炎症应激反应导致2型糖尿病（T2D）胰岛功能障碍。目前还缺乏对这些人类胰岛应激反应以及T2D相关遗传变异是否调节它们的全面基因组理解。

研究人员对离体暴露于这些应激源的人类胰岛的比较转录组和表观基因组分析显示，30%的表达基因和14%的胰岛顺式调节元件（CRE）是应激反应性的，主要以ER或细胞因子特异性的方式进行调节。T2D变异与86个应激反应性CRE重叠，其中21个是由ER应激引起的。

研究人员将rs691766-T T2D风险等位基因与胰岛ER应激反应CRE可及性和等位基因特异性β细胞核因子结合的增加联系起来。MAP3K5是ER应激反应的推定rs6917676 T2D效应基因，促进应激诱导的β细胞凋亡。支持其促糖尿病作用，MAP3K5表达与人胰岛β细胞丰度呈负相关，并在T2Dβ细胞中升高。

总之，这一研究为人类胰岛应激反应和特定背景的T2D变异效应提供了全基因组的见解。

附：英文原文

Title: Multi-omic human pancreatic islet endoplasmic reticulum and cytokine stress response mapping provides type 2 diabetes genetic insights

Author: Eishani K. Sokolowski, Romy Kursawe, Vijay Selvam, Redwan M. Bhuiyan, Asa Thibodeau, Chi Zhao, Cassandra N. Spracklen, Duygu Ucar, Michael L. Stitzel

Issue&Volume: 2024-10-08

Abstract: Endoplasmic reticulum (ER) and inflammatory stress responses contribute to islet dysfunction in type 2 diabetes (T2D). Comprehensive genomic understanding of these human islet stress responses and whether T2D-associated genetic variants modulate them is lacking. Here, comparative transcriptome and epigenome analyses of human islets exposed ex vivo to these stressors revealed 30% of expressed genes and 14% of islet cis-regulatory elements (CREs) as stress responsive, modulated largely in an ER- or cytokine-specific fashion. T2D variants overlapped 86 stress-responsive CREs, including 21 induced by ER stress. We linked the rs6917676-T T2D risk allele to increased islet ER-stress-responsive CRE accessibility and allele-specific β cell nuclear factor binding. MAP3K5, the ER-stress-responsive putative rs6917676 T2D effector gene, promoted stress-induced β cell apoptosis. Supporting its pro-diabetogenic role, MAP3K5 expression correlated inversely with human islet β cell abundance and was elevated in T2D β cells. This study provides genome-wide insights into human islet stress responses and context-specific T2D variant effects.

DOI: 10.1016/j.cmet.2024.09.006

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00370-X