Journal
NATURE GENETICS
Volume 50, Issue 4, Pages 591-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0073-4
Keywords
-
Categories
Funding
- Van Andel Research Institute
- Cedars-Sinai Center for Bioinformatics and Functional Genomics
- Samuel Oschin Comprehensive Cancer Institute
- University of Southern California USC Epigenome Center
- National Institutes of Health/National Cancer Institute grants [U24 CA143882, R01 CA170550, U01 CA184826, U24 CA210969]
- Ovarian Cancer Research Fund Grant [373933]
- National Institutes of Health/National Human Genome Research Institute grant [R01 HG006705]
Ask authors/readers for more resources
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 wholegenome 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available