Genome-wide Analysis of Histone Methylations in Memory CD8+ T Cells. Homo sapiens

Histone methylations play a major role in regulating the chromatin state and gene expression, yet little is known about their involvement in differential gene expression and function of memory CD8 T cells. Here, we report a genome-wide analysis of two histone H3 methylations (H3K4me3 and H3K27me3) and gene expression in naïve, central (TCM) and effector (TEM) memory CD8 T cells. Analysis of 16,314 annotated genes in CD8 T cell subsets revealed that gene expression were positively correlated with the levels of H3K4me3 and negatively correlated with the levels of H3K27me3 in these gene loci. The correlation between differential H3K4me3 orH3K27me3 levels with gene expressions in memory CD8 T cells displayed four distinct modes: repressive, active, poised, and bivalent, reflecting their complex regulation and different function of these genes. Furthermore, accessible chromatin states of different gene loci were preferentially influenced by different histone modifications as demonstrated here high levels of H3K9ac found in active gene loci without high levels of H3K4me3. These findings reveal a histone methylation based complex regulation of differential gene expression in memory CD8 T cells. Thus, change of chromatin structure mediated by histone methylation may serve a fundamental basis for the rapid transcriptional response of memory CD8 T cells. Overall design: genome-wide analysis of two histone H3 methylations (H3K4me3 and H3K27me3) in naïve, central (TCM) and effector (TEM) memory CD8 T cells.

组蛋白甲基化（histone methylation）在调控染色质状态（chromatin state）与基因表达（gene expression）过程中发挥关键作用，但目前对其参与记忆性CD8 T细胞（memory CD8 T cell）的差异基因表达与功能调控的认知仍较为匮乏。本研究针对初始态、中枢记忆性（TCM）及效应性记忆性（TEM）CD8 T细胞，开展了两种组蛋白H3甲基化修饰（H3K4me3与H3K27me3）及基因表达的全基因组分析。对CD8 T细胞亚群中16314个已注释基因的分析显示，对应基因位点的H3K4me3水平与基因表达呈正相关，而H3K27me3水平则与基因表达呈负相关。记忆性CD8 T细胞中，差异H3K4me3或H3K27me3水平与基因表达的关联模式可分为四类：抑制型、激活型、预激活型（poised）与二价型（bivalent），这反映了相关基因的复杂调控机制与功能多样性。此外，不同基因位点的开放染色质状态优先受不同组蛋白修饰的调控；本研究证实，在未伴随高H3K4me3水平的激活基因位点中，可检测到高丰度的H3K9ac修饰。本研究揭示了基于组蛋白甲基化的记忆性CD8 T细胞差异基因表达的复杂调控网络。由此可见，组蛋白甲基化介导的染色质结构重塑，可能是记忆性CD8 T细胞快速转录应答的核心分子基础。实验设计概述：针对初始态、中枢记忆性（TCM）及效应性记忆性（TEM）CD8 T细胞，开展两种组蛋白H3甲基化修饰（H3K4me3与H3K27me3）的全基因组分析。