Abstract 5327: DNA methylation loss in late-replicating domains is linked to mitotic cell division (original) (raw)

Cancer Research, 2018

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”) revealed previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increases with age in both fetal and postnatal tissues, appearing to track accumulation of cell divisions beginning early in life. In cancer, the degree of PMD hypomethylation correlates with somatic mutation density and expression of cell-cycle dependent genes, reinforcing its mitotic clock-like role. We propose that late replication leads to progressive methylation loss throughout a...

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