Yu Kang, Davidson Chelsea E, Burshtyn Deborah N
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada;
J Immunol. 2020 Jun 1;204(11):3030-3041. doi: 10.4049/jimmunol.2000164. Epub 2020 Apr 22.
LILRB1 is a highly polymorphic receptor expressed by subsets of innate and adaptive immune cells associated with viral and autoimmune diseases and targeted by pathogens for immune evasion. LILRB1 expression on human NK cells is variegated, and the frequency of LILRB1 cells differs among people. However, little is known about the processes and factors mediating LILRB1 transcription in NK cells. LILRB1 gene expression in lymphoid and myeloid cells arises from two distinct promoters that are separated by the first exon and intron. In this study, we identified a polymorphic 3-kb region within LILRB1 intron 1 that is epigenetically marked as an active enhancer in human lymphoid cells and not monocytes. This region possesses multiple YY1 sites, and complexes of the promoter/enhancer combination were isolated using anti-YY1 in chromatin immunoprecipitation-loop. CRISPR-mediated deletion of the 3-kb region lowers LILRB1 expression in human NKL cells. Together, these results indicate the enhancer in intron 1 binds YY1 and suggest YY1 provides a scaffold function enabling enhancer function in regulating LILRB1 gene transcription in human NK cells.
LILRB1是一种高度多态性的受体，由与病毒和自身免疫性疾病相关的先天性和适应性免疫细胞亚群表达，并被病原体靶向用于免疫逃避。LILRB1在人类自然杀伤细胞（NK细胞）上的表达是多样的，且LILRB1阳性细胞的频率在不同个体之间存在差异。然而，关于介导NK细胞中LILRB1转录的过程和因素知之甚少。LILRB1基因在淋巴细胞和髓细胞中的表达源自两个不同的启动子，它们被第一个外显子和内含子隔开。在本研究中，我们在LILRB1内含子1中鉴定出一个3kb的多态性区域，该区域在表观遗传上被标记为人类淋巴细胞而非单核细胞中的活性增强子。该区域具有多个YY1位点，并且在染色质免疫沉淀环中使用抗YY1分离出启动子/增强子组合的复合物。CRISPR介导的3kb区域缺失降低了人类NKL细胞中LILRB1的表达。总之，这些结果表明内含子1中的增强子与YY1结合，并提示YY1提供了一种支架功能，使得增强子能够在调节人类NK细胞中LILRB1基因转录方面发挥作用。
