Department of Ophthalmology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
Cell Genom. 2024 Jan 10;4(1):100460. doi: 10.1016/j.xgen.2023.100460. Epub 2023 Dec 5.
Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.
单核苷酸多态性（SNPs）附近的 ERAP2 基因与各种自身免疫性疾病有关，也能预防致命感染。由于高度连锁不平衡，许多与表型相关的 SNPs 与 ERAP2 表达相关；然而，其功能机制仍未确定。我们通过相互等位基因替换表明，ERAP2 的表达是由剪接区变异 rs2248374 直接控制的。然而，下游 LNPEP 基因启动子中的疾病相关变异与 ERAP2 表达独立相关。等位基因特异性构象捕获实验揭示了 LNPEP 和 ERAP2 基因启动子之间的长程染色质接触，并且表明在携带增加自身免疫性疾病易感性等位基因的患者中，相互作用更强。用参考序列替换 LNPEP 启动子中的 SNPs 降低了 ERAP2 的表达。这些发现表明，多个 SNPs 协同作用调节 ERAP2 的表达，并且与疾病相关的变异可以将基因启动子区域转化为远端基因的有效增强子。
