美国宾夕法尼亚大学Golnaz Vahedi研究团队研究发现出在1型糖尿病遗传变异重新配置T细胞的3D染色质组织并改变基因表达。这一研究成果2020年2月11日发表在国际学术期刊《免疫》上。

他们检查了基因组组织是否对序列变异提供了适应力或易感性，以及这将如何导致自身免疫性疾病的分子病因学。他们在NOD小鼠、1型糖尿病（T1D）模型和抗糖尿病C57BL / 6小鼠的胸腺细胞中产生了线性和3D基因组组织的高分辨率图谱。在基因组区域形成多增强子相互作用，该基因组区域包含在两种菌株的T细胞发育中具有突出作用的基因。但是，赋予糖尿病风险的基因座在NOD小鼠胸腺细胞中合并了增强子和启动子，但在C57BL / 6图54中却没有。 NODxC57BL / 6 F1胸腺细胞的3D基因组图谱显示，NOD小鼠的基因组错误折叠是顺式介导的。此外，用T1D浸润人类胰腺的免疫细胞显示位于小鼠错误折叠的基因座上的基因表达增加。因此，遗传变异会导致3D染色质结构改变以及基因表达的相关变化，这些可能是自身免疫病理学的基础。

研究人员表示，遗传学是自身免疫性疾病易感性的主要决定因素。

附：英文原文

Title: Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression

Author: Maria Fasolino, Naomi Goldman, Wenliang Wang, Benjamin Cattau, Yeqiao Zhou, Jelena Petrovic, Verena M. Link, Allison Cote, Aditi Chandra, Michael Silverman, Eric F. Joyce, Shawn C. Little, Klaus H. Kaestner, Ali Naji, Arjun Raj, Jorge Henao-Mejia, Robert B. Faryabi, Golnaz Vahedi

Issue&Volume: February 11, 2020

Abstract: Genetics is a major determinant of susceptibility to autoimmune disorders. Here, weexamined whether genome organization provides resilience or susceptibility to sequencevariations, and how this would contribute to the molecular etiology of an autoimmunedisease. We generated high-resolution maps of linear and 3D genome organization inthymocytes of NOD mice, a model of type 1 diabetes (T1D), and the diabetes-resistantC57BL/6 mice. Multi-enhancer interactions formed at genomic regions harboring geneswith prominent roles in T cell development in both strains. However, diabetes risk-conferringloci coalesced enhancers and promoters in NOD, but not C57BL/6 thymocytes. 3D genomemapping of NODxC57BL/6 F1 thymocytes revealed that genomic misfolding in NOD miceis mediated in cis. Moreover, immune cells infiltrating the pancreas of humans with T1D exhibited increasedexpression of genes located on misfolded loci in mice. Thus, genetic variation leadsto altered 3D chromatin architecture and associated changes in gene expression thatmay underlie autoimmune pathology.

DOI: 10.1016/j.immuni.2020.01.003

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30030-3