Defining CD4 T Cell Memory by the Epigenetic Landscape of CpG DNA Methylation [RNA-Seq]

Memory T cells are primed for rapid responses to antigen; however, the molecular mechanisms responsible for priming remain incompletely defined. CpG methylation in promoters is an epigenetic modification, which regulates gene transcription. Using targeted bisulfite sequencing, we examined methylation of 2100 genes (56,000 CpG) mapped by deep sequencing to T cell activation in human naïve and memory CD4 T cells. 466 CpGs (132 genes) displayed differential methylation between naïve and memory cells. 21 genes exhibited both differential methylation and gene expression before activation, linking promoter DNA methylation states to gene regulation; 6 genes encode proteins closely studied in T cells while 15 genes represent novel targets for further study. 39 genes exhibited reduced methylation in memory cells coupled with increased gene expression with activation compared to naïve cells, revealing specific genes more rapidly expressed in memory compared to naïve cells and potentially regulated by DNA methylation. These findings define a DNA methylation signature unique to memory CD4 T cells and correlated with activation-induced gene expression.记忆T细胞（Memory T cells）已被预编程以实现对抗原的快速应答，但介导其预编程的分子机制仍未完全阐明。启动子区域的CpG甲基化是一种表观遗传修饰，可调控基因转录。本研究采用靶向亚硫酸氢盐测序技术，对人类幼稚CD4 T细胞与记忆CD4 T细胞中，经深度测序定位到T细胞激活相关的2100个基因（共计56000个CpG位点）的甲基化水平进行了检测。在幼稚细胞与记忆细胞之间，共有466个CpG位点（对应132个基因）呈现出差异甲基化特征。其中21个基因在细胞激活前同时存在差异甲基化与基因表达差异，将启动子DNA甲基化状态与基因调控关联起来；6个基因编码的蛋白在T细胞中已有广泛研究，剩余15个基因则为可供后续研究的全新靶点。另有39个基因在记忆细胞中甲基化水平降低，且相较于幼稚细胞，其在激活后的基因表达水平上调，这揭示了一类在记忆T细胞中可更快表达、且可能受DNA甲基化调控的特异性基因。本研究的发现确立了记忆CD4 T细胞所特有的DNA甲基化特征谱，并将其与激活诱导的基因表达相关联。