CpG sites associated with NRP1, NRXN2 and miR-29b-2 are hypomethylated in monocytes during ageing

Abstract

BackgroundAgeing affects many components of the immune system, including innate immune cells like monocytes. They are important in the early response to pathogens and for their role to differentiate into macrophages and dendritic cells. Recent studies have revealed significant age-related changes in genomic DNA methylation in peripheral blood mononuclear cells, however information on epigenetic changes in specific leukocyte subsets is still lacking. Here, we aimed to analyse DNA methylation in purified monocyte populations from young and elderly individuals.FindingsWe analysed the methylation changes in monocytes purified from young and elderly individuals using the HumanMethylation450 BeadChip array. Interestingly, we found that among 26 differentially methylated CpG sites, the majority of sites were hypomethylated in elderly individuals. The most hypomethylated CpG sites were located in neuropilin 1 (NRP1; cg24892069) and neurexin 2 (NRXN2; cg27209729) genes, and upstream of miR-29b-2 gene (cg10501210). The age-related hypomethylation of these three sites was confirmed in a separate group of young and elderly individuals.ConclusionsWe identified significant age-related hypomethylation in human purified monocytes at CpG sites within the regions of NRP1, NRXN2 and miR-29b-2 genes.

Age-related Differences in Monocyte DNA Methylation and Immune Function in Healthy Kenyan Adults and Children

“…Using a threshold for absolute beta value difference of 0.15, we identified 14,259 differentially methylated CpG sites, with 11,535 sites hyper-methylated in adults vs. children and 2,724 hypo-methylated in adults vs. children (P < 0.01, FDR-adjusted P < 0.05) ( Figure 1B; Additional file 2). (10,13,29) as well as whole blood (20,21,33) (Table 1; Additional file 2). For example, we found hyper-methylation in adults vs. children at the site cg22454769 in the FHL2 locus, and similar findings of hyper-methylation with older age have been reported in whole blood samples (20,21) as well as in studies of isolated monocytes by Tserel et al (29) and Saare et al (10).…”

“…Most studies of age-related DNA methylation changes have used whole blood or other mixed cell samples, and few have studied methylation changes in purified monocyte samples (10,12,13,(29)(30)(31). Studies of age-associated methylation patterns in purified T cells and monocytes from the same individuals showed distinct methylation changes in T cells vs. monocytes and emphasize the importance of studying isolated cell populations (12,13).…”

“…Additionally, it is important to take into account the influence that genetic factors and geneenvironment interactions have on the aging epigenome, yet the majority of studies on age-related methylation markers have been performed in populations with European ancestry, and few have been performed in African populations (32,33). Here, we aimed to analyze DNA methylation profiles and innate immune phenotypes and functions of purified monocytes from healthy individuals living in western Kenya, comparing children aged 1-9 years to adults aged [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] years. Participants for this study were enrolled in a larger observational cohort study of naturally acquired immunity to malaria (34,35).…”

Effect of aging on microRNAs and regulation of pathogen recognition receptors

“…Particularly well studied are the miR-29 family members, which have been identified as critical suppressors of key immunological pathways. MiR-29 is expressed in both T and B lymphocytes, in the accessory cell types of thymic epithelium, and in DCs [22, 23]. In DCs, miR-29 is upregulated in response to NOD2 signals, and modulates expression of multiple immune mediators [24]; in macrophages it modulates functional polarization inducing IL-6, TNFα and CXCL9 expression [25].…”

“…Thus, mechanisms controlling resolution of acute inflammation are crucial especially in aging and age-related diseases, since resolution failure can induce many classic and non-classic age-related inflammatory conditions. Notably, an age-related hypomethylation upstream of the miR-29b gene was recently reported in monocytes [23] and an age-associated increase in miR-29b was reported in brains of mice [41]. In macrophages and brain microglia, miR-29b functions through inhibition of the anti-inflammatory protein TNFAIP3, leading to sustained activation of NF-κB and induction of IL-6 and TNF-α production (Figure 1) [25, 66].…”