Liu Ying, Kuick Rork, Hanash Samir, Richardson Bruce
Department of Medicine, University of Michigan, USA.
Clin Immunol. 2009 Feb;130(2):213-24. doi: 10.1016/j.clim.2008.08.009. Epub 2008 Oct 22.
Killer-cell immunoglobulin-like receptor (KIR) genes are a polymorphic family expressed on NK cells, and "senescent" CD28- T cells implicated in cardiovascular disease. KIR promoters are highly homologous, and NK expression is regulated by DNA methylation. T cell KIR regulation is poorly understood. We asked if epigenetic mechanisms and/or transcription factor alterations determine T cell KIR expression. DNA methylation inhibition activated multiple KIR genes in normal T cells. KIR2DL2 and KIR2DL4 were selected for further study. Expression of both was associated with promoter demethylation, and methylation of the promoters in reporter constructs suppressed expression. KIR reporter construct expression also increased in demethylated T cells and required Ets1, Sp1 and AML sites, implying effects on transcription factors. This was confirmed for Sp1. These results indicate that KIR genes are suppressed by DNA methylation in most T cells, and DNA demethylation promotes their expression through effects on both chromatin structure and transcription factors.
杀伤细胞免疫球蛋白样受体（KIR）基因是一个多态性家族，在自然杀伤细胞（NK细胞）上表达，并且“衰老的”CD28阴性T细胞与心血管疾病有关。KIR启动子高度同源，NK细胞的表达受DNA甲基化调控。T细胞中KIR的调控机制尚不清楚。我们探究了表观遗传机制和/或转录因子改变是否决定T细胞KIR的表达。DNA甲基化抑制可激活正常T细胞中的多个KIR基因。我们选择了KIR2DL2和KIR2DL4进行进一步研究。二者的表达均与启动子去甲基化相关，并且报告基因构建体中启动子的甲基化会抑制表达。去甲基化的T细胞中KIR报告基因构建体的表达也会增加，且需要Ets1、Sp1和AML位点，这意味着对转录因子有影响。对Sp1的研究证实了这一点。这些结果表明，在大多数T细胞中，KIR基因被DNA甲基化所抑制，而DNA去甲基化通过对染色质结构和转录因子的作用促进其表达。
