DNA methylation loss in late-replicating domains is linked to mitotic cell division.

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 Genet

journal_title

Nature genetics

authors

Zhou W,Dinh HQ,Ramjan Z,Weisenberger DJ,Nicolet CM,Shen H,Laird PW,Berman BP

doi

10.1038/s41588-018-0073-4

subject

Has Abstract

pub_date

2018-04-01 00:00:00

pages

591-602

issue

4

eissn

1061-4036

issn

1546-1718

pii

10.1038/s41588-018-0073-4

journal_volume

50

pub_type

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