The DOI matches its Crossref record; 77 of the 78 references it cites were found in a registry or an index.
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]
In the citing paper
“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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Citations
Cites
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Self-citationVariation in cancer risk among tissues can be explained by the number of stem cell divisions
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“These regions are known to exhibit reduced fidelity of DNA methylation maintenance during replication, likely due to limited activity of the DNMT1–UHRF1 machinery in late S phase and have been associated with increased epigenetic variability [20–22].”
Ding, X., Mao, Y., Zhang, Y., Yan, Q., Wu, P., Xu, Y. A. N. G., Yu, J., Shi, Q., & Nie, W.-F. (2026) · Journal of Advanced Research · doi:10.1016/j.jare.2026.07.051
Ali, T., & Cao, Q. (2026) · Epigenetics Reports · doi:10.1080/28361512.2026.2720072
Xiao, H., Liu, J., Zhao, J., Liu, X., Wang, B., Zeng, X., Li, Y., Li, Y., Dong, J., Cui, M., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2608386123
Replicative history as a major determinant of epigenetic noise across human tissuesPreprint
Peñarroya, A., Alba‐Linares, J. J., Pérez, R. F., Fernández, A. F., Fraga, M. F., & Tejedor, J. R. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.19.745715
“In addition, complementary mitotic clocks, such as epiTOC[49], based on 385 age-hypermethylated CpG, and HypoClock[28], based on 678 hypomethylated CpG in partially methylated domains[41], were used to further validate estimates of mitotic parameters.”
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“This is relevant to cancer due to the fact that repeated cell division increases opportunities for replication errors, methylation drift, and clonal expansion [11,12].”
Gene regulatory mechanisms downstream of DNA methylation
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InfluentialDNA methylation maintenance at heterochromatin
Wassing, I. E., & Funabiki, H. (2026) · DNA repair · doi:10.1016/j.dnarep.2026.103965
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“The results are also intriguing in the setting of recent observations that WCGW (W = A/T) sites are the most likely to lose methylation in cancer [ 59 ], suggesting that some sites might be more susceptible to DNA demethylation by both active TET-dependent and passive replication-dependent means […”
Self-citationMitigating genotype-driven bias improves atlas-scale single-cell DNA methylome profilingPreprint
Song, X., Diacofotaki, A., van der Veer, B. K., Leroy, K., Aerden, M., Che, H., & Thienpont, B. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.14.756197
Multi-omics atlas of chronic exercise
Maier, G., Hariharan, M., Ramasamy, R. K., Glina, A., van Rosmalen, L., Pathak, S. J., Deota, S., Patel, S., Lin, T., Lam, M. T. Y., et al. (2026) · Cell · doi:10.1016/j.cell.2026.09.044
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“As representative regions of global hypomethylation, PMDs are closely associated with genomic instability [15].”
Magrangeas, F., Cherkaoui, M., Bessonneau-Gaborit, V., Derrien, J., Chevalier, C., Guérin-Charbonnel, C., Diamond, B., Samur, M. K., (IFM), I. F. D. M., Hulin, C., et al. (2026) · Nature Medicine · doi:10.1038/s41591-026-04692-0
Epigenomic heterogeneity and spatial organization during human reprogrammingPreprint
Li, T. W., Langerman, J., Liu, C., Sun, Y., Baig, M. S., Kim, G., Fu, J., Ghoor, R. I., Zhang, Y., Behren, Z. V., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.15.757424
Zhou, W. (2025) · Zenodo (CERN European Organization for Nuclear Research) · doi:10.5281/zenodo.17632460
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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
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