Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs

Abstract

Aging is a progressive process that results in the accumulation of intra- and extracellular alterations that in turn contribute to a reduction in health. Age-related changes in DNA methylation have been reported before and may be responsible for aging-induced changes in gene expression, although a causal relationship has yet to be shown. Using genome-wide assays, we analyzed age-induced changes in DNA methylation and their effect on gene expression with and without transient induction with the synthetic transcription modulating agent WY14,643. To demonstrate feasibility of the approach, we isolated peripheral blood mononucleated cells (PBMCs) from five young and five old healthy male volunteers and cultured them with or without WY14,643. Infinium 450K BeadChip and Affymetrix Human Gene 1.1 ST expression array analysis revealed significant differential methylation of at least 5 % (ΔYO > 5 %) at 10,625 CpG sites between young and old subjects, but only a subset of the associated genes were also differentially expressed. Age-related differential methylation of previously reported epigenetic biomarkers of aging including ELOVL2, FHL2, PENK, and KLF14 was confirmed in our study, but these genes did not display an age-related change in gene expression in PBMCs. Bioinformatic analysis revealed that differentially methylated genes that lack an age-related expression change predominantly represent genes involved in carcinogenesis and developmental processes, and expression of most of these genes were silenced in PBMCs. No changes in DNA methylation were found in genes displaying transiently induced changes in gene expression. In conclusion, aging-induced differential methylation often targets developmental genes and occurs mostly without change in gene expression.Electronic supplementary materialThe online version of this article (doi:10.1007/s11357-014-9648-x) contains supplementary material, which is available to authorized users.

Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes

“…The aDMRs and aGENs from different studies were largely non-overlapping (Tables S1 and S2, Fig. S1, the fact also discussed in 16 ), with only one aDMR being identified in 7 studies and 335 out of 16,854 aDMRs detected by 3 studies. These results suggest that different studies may point toward study-specific age-related epigenomic associations.…”

“…Each cell shows the numerical value of the corresponding Spearman correlation coefficient. 16 4,552 methylation markers correlated with age-but not with gene expression changes in peripheral blood Steegenga_aDMRs_meta 16 7,477 age-associated methylation markers identified in multiple studies Heyn_aDMRs 11 3,205 age-associated methylation markers differentially methylated in cord blood of newborns and CD4C T cells of centenarian; 1,219 of them showed hypermethylation with age, 1,986 were found to be hypomethylated with age Age-associated genes (aGENs) Hannum_genes_associated 1 326 genes correlated with age by expression, whole blood, data not related to methylation data Hannum_genes_predictive; 1 Hannum_genes_predictive_pos; Hannum_genes_predictive_neg 55 genes predictive of age based by their expression, whole blood, data not related to methylation data. Twenty-four of these genes showed positive correlation with age by expression, 31 were found to be negatively correlated with age Genes_LongevityMap 47 752 manually curated list of age-associated genes deMagalhaes_genes_all; 33 deMagalhaes_genes_pos; deMagalhaes_genes_neg 73 age-associated genes.…”

“…Consistent with the depletion of RNA Polymerase II and activating TFBSs, the "active promoter" chromatin state was among the most depleted. A group of monocytespecific, 15 pediatric-teenager, 7 pediatric-centenarian, 11 and meta aDMRs 16 showed a weaker enrichment in "poised promoter" but a stronger depletion in "active promoter" chromatin states. The "transcriptional elongation" state was uniformly depleted in all sets of aDMRs and aGENs.…”

“…[1][2][3][4] In the last decade, age-associated epigenetic changes attracted significant attention, 5,6 with DNA methylation being the best studied. 1,[7][8][9][10][11][12][13][14][15][16][17] In human subjects, age-related changes in DNA methylation have been detected mostly in whole blood, 1,14,17 in purified subsets of blood, 11,14 and in the brain. 18,19 The relationship of age-related DNA methylation regions (aDMRs) with CpG islands, 9 "bivalent domains," 14 and gene-centric regions, such as promoters, exonic, intronic and intergenic regions, 11 Alu, LINE-1, and other repetitive elements 11,20,21 has been extensively investigated.…”

“…14,[16][17][18] However, methylation and gene expression changes are not necessarily correlated. 1,15,16 We investigated whether similar epigenomic signature(s) are shared by aDMRs that are associated vs. not associated with gene expression changes.…”