DNA甲基化
甲基化
生物
DNA复制
DNA
背景(考古学)
表观遗传学
DNA损伤
分子生物学
细胞生物学
遗传学
基因
基因表达
古生物学
作者
Jamie L. Endicott,Paula A. Nolte,Hui Shen,Peter W. Laird
标识
DOI:10.1038/s41467-022-34268-8
摘要
Abstract DNA methylation undergoes dramatic age-related changes, first described more than four decades ago. Loss of DNA methylation within partially methylated domains (PMDs), late-replicating regions of the genome attached to the nuclear lamina, advances with age in normal tissues, and is further exacerbated in cancer. We present here experimental evidence that this DNA hypomethylation is directly driven by proliferation-associated DNA replication. Within PMDs, loss of DNA methylation at low-density CpGs in A:T-rich immediate context (PMD solo-WCGWs) tracks cumulative population doublings in primary cell culture. Cell cycle deceleration results in a proportional decrease in the rate of DNA hypomethylation. Blocking DNA replication via Mitomycin C treatment halts methylation loss. Loss of methylation continues unabated after TERT immortalization until finally reaching a severely hypomethylated equilibrium. Ambient oxygen culture conditions increases the rate of methylation loss compared to low-oxygen conditions, suggesting that some methylation loss may occur during unscheduled, oxidative damage repair-associated DNA synthesis. Finally, we present and validate a model to estimate the relative cumulative replicative histories of human cells, which we call “RepliTali” ( Repli cation T imes A ccumulated in Li fetime).
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