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

Wanding Zhou, Huy Q. Dinh, Zachary Ramjan, Daniel J. Weisenberger, Charles M. Nicolet, Hui Shen*, Peter W. Laird, Benjamin P. Berman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

204 Scopus citations

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.

Original languageAmerican English
Pages (from-to)591-602
Number of pages12
JournalNature Genetics
Volume50
Issue number4
DOIs
StatePublished - 1 Apr 2018
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

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