The impact of healthy aging on molecular programming of immune cells is poorly understood. Here, we report comprehensive characterization of healthy aging in human classical monocytes, with a focus on epigenomic, transcriptomic, and proteomic alterations, as well as the corresponding proteomic and metabolomic data for plasma, using healthy cohorts of 20 young and 20 older individuals (~27 and ~64 years old on average). For each individual, we performed eRRBS-based DNA methylation profiling, which allowed us to identify a set of age-associated differentially methylated regions (DMRs) – a novel, cell-type specific signature of aging in DNA methylome. Optimized ultra-low-input ChIP-seq (ULI-ChIP-seq) data acquisition and analysis pipelines applied to 5 chromatin marks for each individual revealed lack of large-scale age-associated changes in chromatin modifications and allowed us to link hypo- and hypermethylated DMRs to distinct chromatin modification patterns. Specifically, hypermethylation events were associated with H3K27me3 in the CpG islands near promoters of lowly-expressed genes, while hypomethylated DMRs were enriched in H3K4me1 marked regions and associated with normal pattern of expression. Furthermore, hypo- and hypermethylated DMRs followed distinct functional and genetic association patterns. Hypomethylation events were associated with age-related increase of expression of the corresponding genes, providing a link between DNA methylation and age-associated transcriptional changes in primary human cells. Furthermore, these locations were also enriched in genetic regions associated by GWAS with asthma, total blood protein, hemoglobin levels and MS. On the other side, acceleration of epigenetic age in HIV and asthma stems only from changes in hypermethylated DMRs but not from hypomethylated loci.

中文翻译：

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来自健康个体的经​​典单核细胞的表观遗传衰老

健康衰老对免疫细胞分子程序的影响知之甚少。在这里，我们报告了使用20名年轻和20名年龄较大的个体的健康人群（〜），对人类经典单核细胞健康衰老的全面表征，重点是表观基因组学，转录组学和蛋白质组学变化以及血浆的相应蛋白质组学和代谢组学数据。平均年龄在27岁和〜64岁之间）。对于每个人，我们都进行了基于eRRBS的DNA甲基化分析，这使我们能够鉴定出一组与年龄相关的差异甲基化区域（DMR）-DNA甲基化中新的细胞类型特异性衰老特征。优化的超低输入ChIP-seq（ULI-ChIP-seq）数据采集和分析管道适用于每个人的5个染色质标记，显示出缺乏与年龄相关的大规模染色质修饰变化，并允许我们将次假设和次要关联高甲基化的DMRs形成独特的染色质修饰模式。具体而言，高甲基化事件与低表达基因启动子附近的CpG岛中的H3K27me3相关，而低甲基化DMR则富含H3K4me1标记的区域并与正常表达模式相关。此外，低甲基化和高甲基化的DMR遵循不同的功能和遗传关联模式。次甲基化事件与年龄相关基因表达的增加有关，在原代人类细胞中提供DNA甲基化与年龄相关的转录变化之间的联系。此外，这些位置还丰富了与哮喘，总血蛋白，血红蛋白水平和MS相关的GWAS相关遗传区域。另一方面，HIV和哮喘中表观遗传年龄的加速仅源自甲基化过高的DMR的变化，而不是源自甲基化过低的基因座。