Nature Communications ( IF 14.7 ) Pub Date : 2023-03-03 , DOI: 10.1038/s41467-023-36897-z Zhao Wang 1, 2, 3 , Qian Liang 2, 4 , Xinyi Qian 2 , Bolang Hu 3 , Zhanye Zheng 2 , Jianhua Wang 1 , Yuelin Hu 3 , Zhengkai Bao 3 , Ke Zhao 2 , Yao Zhou 1 , Xiangling Feng 2 , Xianfu Yi 1, 5 , Jin Li 6 , Jiandang Shi 7 , Zhe Liu 8 , Jihui Hao 9 , Kexin Chen 10 , Ying Yu 2 , Pak Chung Sham 11 , Wange Lu 7 , Xiaoyan Wang 12 , Weihong Song 3 , Mulin Jun Li 1, 2, 10
Genetic sharing is extensively observed for autoimmune diseases, but the causal variants and their underlying molecular mechanisms remain largely unknown. Through systematic investigation of autoimmune disease pleiotropic loci, we found most of these shared genetic effects are transmitted from regulatory code. We used an evidence-based strategy to functionally prioritize causal pleiotropic variants and identify their target genes. A top-ranked pleiotropic variant, rs4728142, yielded many lines of evidence as being causal. Mechanistically, the rs4728142-containing region interacts with the IRF5 alternative promoter in an allele-specific manner and orchestrates its upstream enhancer to regulate IRF5 alternative promoter usage through chromatin looping. A putative structural regulator, ZBTB3, mediates the allele-specific loop to promote IRF5-short transcript expression at the rs4728142 risk allele, resulting in IRF5 overactivation and M1 macrophage polarization. Together, our findings establish a causal mechanism between the regulatory variant and fine-scale molecular phenotype underlying the dysfunction of pleiotropic genes in human autoimmunity.
中文翻译:
自身免疫多效性 SNP 通过 ZBTB3 介导的染色质环调节 IRF5 替代启动子的使用
广泛观察到自身免疫性疾病的遗传共享,但致病变异及其潜在的分子机制在很大程度上仍然未知。通过对自身免疫性疾病多效性位点的系统研究,我们发现这些共有的遗传效应大部分是通过调控密码传递的。我们使用基于证据的策略在功能上对因果多效性变异进行优先排序并确定其目标基因。排名靠前的多效性变体 rs4728142 产生了许多因果关系证据。从机制上讲,包含 rs4728142 的区域以等位基因特异性方式与IRF5替代启动子相互作用,并协调其上游增强子来调节IRF5通过染色质循环替代启动子的使用。推定的结构调节因子 ZBTB3 介导等位基因特异性环以促进rs4728142 风险等位基因处的IRF5短转录物表达,导致IRF5过度激活和 M1 巨噬细胞极化。总之,我们的研究结果建立了人类自身免疫中多效基因功能障碍的调节变异和精细分子表型之间的因果机制。