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DNA methylation loss in late-replicating domains is linked to mitotic cell division
Open accessAbstract
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.
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“It is known that aged cells (and cancer cells) generally lose DNA methylation from gene bodies59”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [59]
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“Old yeast cells have decreased H3K36me3 levels and increased intragenic transcripts58, while DNA methylation decreases with age in humans59.”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [59]
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“Analysis of the whole genome methylomes of 39 primary tumors in mouse and human shows a pronounced loss of methylation at nuclear lamina associated partially methylated domains (PMDs) located in late replicating parts of the genome (44).”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [44]
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Metadata
- Authors
- Zhou, W., Dinh, H. Q., Ramjan, Z., Weisenberger, D. J., Nicolet, C. M., Shen, H., Laird, P. W., & Berman, B. P.
- Affiliations
- Van Andel Institute (US)
- Cedars-Sinai Medical Center (US)
- University of Southern California (US)
- Corresponding author
- Shen, Hui
- Laird, Peter W.
- Berman, Benjamin P.
- ORCID
- Venue
- Nature Genetics
- Published
- 2018-04
- Volume
- 50
- Issue
- 4
- Pages
- 591-602
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5893360
- OpenAlex
- W2795164082
- Cited by
- 405
- References
- 78
- Citations by year
- 2026: 40 · 2025: 52 · 2024: 58 · 2023: 59 · 2022: 55 · 2021: 57 · 2020: 43 · 2019: 26 · 2018: 15
- FWCI
- 12.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Ovarian Cancer Research Fund (373933)
- University of Southern California
- Cedars-Sinai Medical Center
- National Institutes of Health
- National Human Genome Research Institute (R01HG006705)
- National Cancer Institute (U24CA143882, R01CA170550, CA184826, U24CA210969, U01CA184826)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- DNA methylation loss, partially methylated domains, cellular aging, cell cycle gene expression, cancer epigenetics, fetal development, carcinogenesis, age-related methylation
- MeSH terms
- Whole Genome Sequencing, Aging, Animals, Cell Division, DNA Replication, DNA, Neoplasm, Female, Humans, Male, Mitosis, Neoplasms, Pregnancy, CpG Islands, DNA Methylation, Embryonic Development, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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