Integrative analysis of methylome and transcriptome in human blood identifies extensive sex- and immune cell-specific differentially methylated regions

The relationship between DNA methylation and gene expression is complex and elusive. To further elucidate these relations, we performed an integrative analysis of the methylome and transcriptome of 4 circulating immune cell subsets (B cells, monocytes, CD4⁺, and CD8⁺ T cells) from healthy females. Additionally, in light of the known sex bias in the prevalence of several immune-mediated diseases, the female datasets were compared with similar public available male data sets. Immune cell-specific differentially methylated regions (DMRs) were found to be highly similar between sexes, with an average correlation coefficient of 0.82; however, numerous sex-specific DMRs, shared by the cell subsets, were identified, mainly on autosomal chromosomes. This provides a list of highly interesting candidate genes to be studied in disorders with sexual dimorphism, such as autoimmune diseases. Immune cell-specific DMRs were mainly located in the gene body and intergenic region, distant from CpG islands but overlapping with enhancer elements, indicating that distal regulatory elements are important in immune cell specificity. In contrast, sex-specific DMRs were overrepresented in CpG islands, suggesting that the epigenetic regulatory mechanisms of sex and immune cell specificity may differ. Both positive and, more frequently, negative correlations between subset-specific expression and methylation were observed, and cell-specific DMRs of both interactions were associated with similar biological pathways, while sex-specific DMRs were linked to networks of early development or estrogen receptor and immune-related molecules. Our findings of immune cell- and sex-specific methylome and transcriptome profiles provide novel insight on their complex regulatory interactions and may particularly contribute to research of immune-mediated diseases.

DNA甲基化与基因表达的关系复杂且难以厘清。为进一步阐明二者间的关联，本研究对健康女性来源的4种循环免疫细胞亚群（B细胞、单核细胞、CD4阳性T细胞及CD8阳性T细胞）的甲基化组（methylome）与转录组（transcriptome）开展了整合分析。此外，鉴于多种免疫介导疾病的患病率存在已知的性别偏倚，研究团队将女性数据集与公开可得的同类男性数据集进行了比对。结果显示，不同性别间的免疫细胞特异性差异甲基化区域（differentially methylated regions, DMRs）高度相似，平均相关系数达0.82；但同时鉴定出多个由各细胞亚群共有的性别特异性DMR，这些区域主要分布于常染色体上。本研究鉴定的候选基因列表，可为性二态性疾病（如自身免疫性疾病）的相关研究提供极具价值的研究靶点。免疫细胞特异性DMR主要定位于基因本体及基因间区，远离CpG岛但与增强子元件存在重叠，提示远端调控元件在免疫细胞特异性调控中发挥关键作用。与之相反，性别特异性DMR在CpG岛上的富集程度更高，表明性别与免疫细胞特异性的表观遗传调控机制可能存在差异。研究观察到亚群特异性表达与甲基化之间存在正相关及负相关关系，其中负相关更为常见；两类交互作用相关的细胞特异性DMR均富集于相似的生物学通路，而性别特异性DMR则与早期发育通路、雌激素受体及免疫相关分子网络存在关联。本研究关于免疫细胞及性别特异性甲基化组与转录组特征的发现，为二者复杂的调控互作关系提供了全新视角，尤其可为免疫介导疾病的研究提供重要支撑。