Wiencke John K, Butler Rondi, Hsuang George, Eliot Melissa, Kim Stephanie, Sepulveda Manuel A, Siegel Derick, Houseman E Andres, Kelsey Karl T
a Department of Neurological Surgery , University of California San Francisco , San Francisco , CA.
b Brown University , Department of Epidemiology , Providence , RI.
Epigenetics. 2016 May 3;11(5):363-80. doi: 10.1080/15592294.2016.1163454. Epub 2016 Mar 11.
Natural killer (NK) cells are now recognized to exhibit characteristics akin to cells of the adaptive immune system. The generation of adaptive memory is linked to epigenetic reprogramming including alterations in DNA methylation. The study herein found reproducible genome wide DNA methylation changes associated with human NK cell activation. Activation led predominately to CpG hypomethylation (81% of significant loci). Bioinformatics analysis confirmed that non-coding and gene-associated differentially methylated sites (DMS) are enriched for immune related functions (i.e., immune cell activation). Known DNA methylation-regulated immune loci were also identified in activated NK cells (e.g., TNFA, LTA, IL13, CSF2). Twenty-one loci were designated high priority and further investigated as potential markers of NK activation. BHLHE40 was identified as a viable candidate for which a droplet digital PCR assay for demethylation was developed. The assay revealed high demethylation in activated NK cells and low demethylation in naïve NK, T- and B-cells. We conclude the NK cell methylome is plastic with potential for remodeling. The differentially methylated region signature of activated NKs revealed similarities with T cell activation, but also provided unique biomarker candidates of NK activation, which could be useful in epigenome-wide association studies to interrogate the role of NK subtypes in global methylation changes associated with exposures and/or disease states.
自然杀伤（NK）细胞如今被认为具有类似于适应性免疫系统细胞的特征。适应性记忆的产生与表观遗传重编程有关，包括DNA甲基化的改变。本文的研究发现了与人类NK细胞激活相关的可重复的全基因组DNA甲基化变化。激活主要导致CpG低甲基化（81%的显著位点）。生物信息学分析证实，非编码和基因相关的差异甲基化位点（DMS）富含免疫相关功能（即免疫细胞激活）。在活化的NK细胞中也鉴定出了已知的DNA甲基化调节的免疫基因座（如TNFA、LTA、IL13、CSF2）。21个位点被指定为高优先级，并作为NK激活的潜在标志物进行了进一步研究。BHLHE40被确定为一个可行的候选基因，并开发了一种用于去甲基化的液滴数字PCR检测方法。该检测方法显示，活化的NK细胞中去甲基化程度高，而幼稚NK细胞、T细胞和B细胞中去甲基化程度低。我们得出结论，NK细胞甲基化组具有可塑性，具有重塑潜力。活化NK细胞的差异甲基化区域特征揭示了与T细胞激活的相似性，但也提供了NK激活的独特生物标志物候选物，这可能有助于在全表观基因组关联研究中探究NK亚型在与暴露和/或疾病状态相关的全球甲基化变化中的作用。
