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. 2010 Apr;20(4):440–446. doi: 10.1101/gr.103606.109

Figure 1.

Figure 1.

DNAm signatures for aging and enrichment of PCGTs. (A) Flowchart depicting the derivation of the “core” DNA methylation signature for aging. First, the supervised analysis was performed separately for the blood samples from 148 healthy and 113 ovarian cancer cases. This yielded 293 CpGs and 420 CpGs passing a FDR (q) cut-off of 0.3. There was a strong overlap between these two signatures (Fisher's exact test, P = 10−30) with >80% concordance. Healthy and pretreatment samples were thus combined and supervised analysis was performed on this larger set to identify with more confidence a DNA methylation signature for aging. This gave 589 age-associated CpGs (q < 0.05), termed the “core” aging signature. Distribution of these 589 CpGs in terms of hyper- and hypomethylation patterns demonstrated a skew toward hypomethylation (binomial test, P = 6 × 10−9). Among the 226 hypermethylated CpGs, 69 mapped to polycomb group targets (PCGTs) (64 unique gene loci), while among the 363 hypomethylated CpGs this number was only 20 (11 unique gene loci). Thus, relative to the “core” aging signature, PCGTs were preferentially hypermethylated (69 vs. 20 compared with 226 vs. 363, Fisher's exact test, P < 4 × 10−12). Here, PCGTs were defined by promoter occupancy of any one of SUZ12, EED, or H3K27me3 in human embryonic stem cells (Lee et al. 2006). (B,C) Enrichment odds ratios with 95% confidence intervals for PCGTs (B) and for H3K27me3 marks (C), among the 226 age-hypermethylated and 363 age-hypomethylated CpGs. H3K27me3 marks were defined by trimethylation of H3K27 within gene body, promoter, and gene body + promoter regions in CD133+ hematopoietic stem cells (HSC) (Cui et al. 2009). (D,E) Independent validation: enrichment odds ratios with 95% confidence intervals for PCGTs among CpGs undergoing significant hyper- and hypomethylation with age in 188 blood samples from patients with type-1 diabetes (D) and 177 ovarian cancer samples (E). (Dashed line) Line of unit odds ratio. Two-tailed P-values of enrichment (i.e., deviation from this line) are given.