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.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Zhou W,Dinh HQ,Ramjan Z,Weisenberger DJ,Nicolet CM,Shen H,Laird PW,Berman BPdoi
10.1038/s41588-018-0073-4subject
Has Abstractpub_date
2018-04-01 00:00:00pages
591-602issue
4eissn
1061-4036issn
1546-1718pii
10.1038/s41588-018-0073-4journal_volume
50pub_type
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