Abstract
DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed partially methylated domains (PMDs). We profiled 39 diverse primary tumors and 8 matched adjacent tissues using whole-genome bisulfite sequencing (WGBS) and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context (‘solo-WCGWs’) identified previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increased with age, beginning during fetal development, and appeared to track the accumulation of cell divisions. In cancer, PMD hypomethylation depth correlated with somatic mutation density and cell cycle gene expression, consistent with its reflection of mitotic history and suggesting its application as a mitotic clock. We propose that late replication leads to lifelong progressive methylation loss, which acts as a biomarker for cellular aging and which may contribute to oncogenesis.
Highlights
DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed partially methylated domains (PMDs)
We investigated solo-WCGW PMD structure by combining our The Cancer Genome Atlas (TCGA) dataset with 343 previously published human and 206 mouse wholegenome bisulfite sequencing (WGBS) samples (Supplementary Table 1), examining solo-WCGW methylation averages with human samples arranged into six groups (Fig. 3) and mouse samples arranged into four groups (Fig. 4)
Within TCGA tumors, we found that higher genomewide somatic mutation densities were significantly associated with deeper PMD hypomethylation, suggesting that mitotic turnover may underlie both somatic mutation and PMD hypomethylation (Fig. 7b)
Summary
DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed partially methylated domains (PMDs). Genomic studies[5,6,7,8,9] established that hypomethylation occurs in only about half the genome, coinciding with megabase-scale domains of repressive chromatin characterized by low gene density, low GC density, late replication timing, localization at the nuclear lamina, and Hi-C ‘B’ domains[10,11]. These regions were termed PMDs and were contrasted with ‘highly methylated domains’ (HMDs) that make up the remainder of the genome[12]. This reinforced the prevailing view that PMD hypomethylation may be restricted to a very limited set of normal cell types or only initiated upon exposure to environmental factors such as carcinogens[26]
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