Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression
Genetic Variation in Type 1 Diabetes Reconfigures the 3D Chromatin Organization of T Cells and Alters Gene Expression
复制标题
DOI：
10.1016/j.immuni.2020.01.003
复制
发表时间：
2020-02-18
期刊：
影响因子：
32.4
通讯作者：
Vahedi, Golnaz
中科院分区：
文献类型：
--
作者：
Fasolino, Maria;Goldman, Naomi;Vahedi, Golnaz
遗传是自身免疫性疾病易感性的主要决定因素。在这里，我们研究了基因组组织是否提供了对序列变异的弹性或易感性，以及这将如何促进自身免疫性疾病的分子病因学。我们在NOD小鼠、1型糖尿病模型（T1D）和糖尿病抵抗型C57BL/6小鼠的胸腺细胞中生成了线性和3D基因组组织的高分辨率地图。在这两种菌株中，多增强子相互作用在包含在T细胞发育中起重要作用的基因的基因组区域形成。然而，糖尿病风险基因座在NOD中结合了增强子和启动子，而在C57BL/6胸腺细胞中却没有。NODxC57BL/6 F1胸腺细胞的三维基因组图谱显示，NOD小鼠的基因组错误折叠是顺式介导的。此外，浸润T1D患者胰腺的免疫细胞在小鼠中表现出位于错误折叠位点上的基因表达增加。因此，遗传变异导致三维染色质结构的改变和相关的基因表达变化，这可能是自身免疫病理的基础。
Genetics is a major determinant of susceptibility to autoimmune disorders. Here, we examined whether genome organization provides resilience or susceptibility to sequence variations, and how this would contribute to the molecular etiology of an autoimmune disease. We generated high-resolution maps of linear and 3D genome organization in thymocytes of NOD mice, a model of type 1 diabetes (T1D), and the diabetes-resistant C57BL/6 mice. Multi enhancer interactions formed at genomic regions harboring genes with prominent roles in T cell development in both strains. However, diabetes risk-conferring loci coalesced enhancers and promoters in NOD, but not C57BL/6 thymocytes. 3D genome mapping of NODxC57BL/6 F1 thymocytes revealed that genomic misfolding in NOD mice is mediated in cis. Moreover, immune cells infiltrating the pancreas of humans with T1D exhibited increased expression of genes located on misfolded loci in mice. Thus, genetic variation leads to altered 3D chromatin architecture and associated changes in gene expression that may underlie autoimmune pathology.