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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]
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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Integrative modeling identifies genetic ancestry-associated molecular correlates in human cancer
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InfluentialInference of genomic spatial organization from a whole genome bisulfite sequencing samplePreprint
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“…easy to produce to predict the results of more costly experiments has some practical appeal, but it also points the way to a simple quantification of the relation between 1 D and 3 D signal which is probably easy to extend and refine (for example by considering solo-WCGWs as described in [ 19 ]).”
Derrien, J., Guérin‐Charbonnel, C., Gaborit, V., Campion, L., Devic, M., Douillard, E., Roi, N., Avet‐Loiseau, H., Decaux, O., Facon, T. T. F., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.10.01.321943 · Cited by 4
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“Because DNA hypomethylation is associated with chronological age (21), it is important also to consider methylation clocks discovered directly from age association, such as the Horvath pan-tissue aging clock (35) and derivatives.”
BackgroundMethodResultInfluentialSelf-citationInsights into aging from progeroid syndrome epigenetics
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Evolutionary dynamics of 1,976 lymphoid malignancies predict clinical outcomePreprint
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DNMT1 loss leads to hypermethylation of a subset of late replicating domains by DNMT3A
Kafetzopoulos, I., Taglini, F., Pasquier, M., Davidson‐Smith, H., Rodger, C. J., Gimeno, L. P., Malcolm, A. A., & Sproul, D. (2026) · PLoS Genetics · doi:10.1371/journal.pgen.1012098 · Cited by 3
Identification of prognostic biomarkers among ICAMs in the breast cancer microenvironment
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“…was lower than that in the normal group, the methylation level of ICAM1 in BC was negatively correlated with the immune cell infiltration level, and high expression of ICAM1 was associated with better OS and RFS, which was consistent with the research results of Jeschke J and Zhou et al. [48,49].”
Spatiotemporal DNA methylation dynamics shape megabase-scale methylome landscapes
Toh, H., & Sasaki, H. (2024) · Life Science Alliance · doi:10.26508/lsa.202302403 · Cited by 4
“It is hypothesized that regions that replicate early in the S phase, such as compartment A, have increased exposure to methylation maintenance machinery, leading to more extensive methylation than regions that replicate later (Zhou et al, 2018).”
BackgroundMetabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype
Nassiri, F., Ajisebutu, A. A., Patil, V. S., Mamatjan, Y., Liu, J., Wang, J. Z., Voisin, M. R., Nejad, R., Mansouri, S., Karimi, S., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02713-1 · Cited by 5
“We used several previously described methods: epiTOC, epiTOC2, and solo-WCGW (or HypoClock) to calculate the epigenetic mitotic clock of gliomas in our different metabolic groups [32, 37, 38].”
Gautam, V., Duari, S., Solanki, S., Gupta, M., Mittal, A., Arora, S., Aggarwal, A., Sharma, A. K., Tyagi, S., Pankajbhai, R. K., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115270 · Cited by 3
Domain segregated 3D chromatin structure and segmented DNA methylation in carcinogenesisPreprint
Xue, Y., Yang, Y., Tian, H., Quan, H., Liu, S., Zhang, L., & Gao, Y. Q. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.13.903963 · Cited by 3
“We also examined the sequence environment effects on solo-WCGW (‘solo’ refers to the CpGs with no neighboring CpGs and ‘W’ indicates A or T nucleotide), which is reported to be the most hypomethylation-prone sites in carcinogenesis (24) (Supplementary Figure S11).”
BackgroundResultEpigenomic profiling of active regulatory elements by enrichment of unmodified CpG dinucleotidesPreprint
Tosti, L., Mould, C., Gatehouse, I., Camargo, A. V., Smith, A., Ubych, K., Laird, P. W., Kennefick, J., & Neely, R. K. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.16.575381 · Cited by 3
“Partially methylated domains (PMDs) are prevalent in the cancer methylome and are characterised by wide genomic regions (up to megabases) that bear low levels of DNA methylation 18,19,38 .”
BackgroundSelf-citationLiang, C., Ye, P., Yan, H., Zheng, P., Sun, J., Wang, Y., Li, Y., Ren, Y., Jiang, Y., Wei, R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.19.638959 · Cited by 3
“In designing the tokenization approach for methylation data, we considered the impact of DNA background information surrounding CpG sites on methylation (13) .”
Wang, X., Dai, L., Liu, Y., Li, C., Fan, D., Zhou, Y., Li, P., Kong, Q., & Su, J. (2023) · Epigenetics & Chromatin · doi:10.1186/s13072-023-00490-x · Cited by 2
Statistical Models for High-Risk Intestinal Metaplasia with DNA Methylation Profiling
Wang, T., Huang, Y. J., & Yang, J. (2024) · Epigenomes · doi:10.3390/epigenomes8020019 · Cited by 2
Zhang, X., Zhang, W., Zhang, J., Lyu, X., Pan, H., Jia, T., Wang, T., Wang, X., & Guo, H. (2025) · Briefings in Bioinformatics · doi:10.1093/bib/bbaf252 · Cited by 2
“Genome-wide hypomethylation, particularly in CpG-depleted regions such as retrotransposons and solo-WCGW sites, represents another hallmark of cancer and is attributed to impaired methylation maintenance during cell division [33, 34].”
KnowYourCG: Facilitating base-level sparse methylome interpretation
Goldberg, D. C., Fu, H., Atkins, D., Moyer, E. J., Lee, C. N., Deng, Y., & Zhou, W. (2025) · Science Advances · doi:10.1126/sciadv.adw3027 · Cited by 4
“Intergenic methylation is known to implicate cell replication ( 25 , 26 ), genome instability ( 25 – 28 ), cell differentiation ( 2 , 29 ), and aberrant writer/eraser enzyme activity ( 30 , 31 ).”
InfluentialSelf-citationTET CpG sequence-context-specific DNA demethylation shapes progression of IDH-mutant gliomas
Hoogstrate, Y., Ghisai, S. A., van Hijfte, L., Head, R., de Heer, I. J., Padovan, M., de Wit, M., Vallentgoed, W., Dipasquale, A., Wijnenga, M. M. J., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.102682 · Cited by 2
Kerr, L., Sproul, D., & Grima, R. (2022) · Journal of The Royal Society Interface · doi:10.1098/rsif.2021.0707 · Cited by 2
“These include the formation of megabase-sized partially methylated domains in cancer which have been linked to genome instability [27,28].”
BackgroundAge-Related Variation in DNA Methylation
Keith, K., Issa, J. J., & Panjarian, S. B. (2022) · Springer eBooks · doi:10.1007/978-3-030-94475-9_10 · Cited by 2
Monitoring Social Determinants of Health Assessing Patients and Communities
Morelli, V., & Heizelman, R. (2023) · Primary Care Clinics in Office Practice · doi:10.1016/j.pop.2023.04.005 · Cited by 2
Region‐specific DNA hydroxymethylation along the malignant progression of IDH ‐mutant gliomas
Hana, T., Mukasa, A., Nomura, M., Nagae, G., Yamamoto, S., Tatsuno, K., Ueda, H., Fukuda, S., Umeda, T., Tanaka, S., et al. (2024) · Cancer Science · doi:10.1111/cas.16127 · Cited by 2
“16 Conversely, TET-mediated active demethylation, such as hydroxymethylation, has been reported in certain genomic re - gions among high-grade IDH mt gliomas and has potentially been suggested to influence gene expression.”
BackgroundNutriepigenomics: Paving the way for personalized nutrition
Park, Y. J., Song, S., Han, Y., & Lindroth, A. M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23802-4.00014-4 · Cited by 2
Rjh, S., Burger, J. A., & Zain, R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252211968 · Cited by 2
“Global hypomethylation altering chromatin topology has been suggested to represent a ‘mitotic clock’ corresponding to the number of cell divisions in somatic cells [32].”
Toward the DNA methylation haplotype map of 11 common solid cancers
Zhang, Z., Hong, Y., Zhang, S., Zhu, X., Liu, L., Liao, X., Gu, H., Fang, H., & Shi, J. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116197 · Cited by 3
How Epigenomics Broke the Mold: An Interview with Peter W Laird
Laird, P. W. (2022) · Epigenomics · doi:10.2217/epi-2022-0066 · Cited by 2
Self-citationGull, N., Jones, M. R., Peng, P.-C., Coetzee, S. G., Silva, T. C., Plummer, J., Reyes, A. L. P., Davis, B. D., Chen, S., Lawrenson, K., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.25.267161 · Cited by 1
Self-citationMasuelli, S., Real, S., Campoy, E., Branham, M. T., Matías, M. D., Salomon, M. P., Blas, G. A. D., Arias, R., Levin, M. G., & Roqué, M. (2021) · Research Square · doi:10.21203/rs.3.rs-1020823/v1 · Cited by 2
Characterization of epigenetic alterations in esophageal cancer by whole-genome bisulfite sequencingPreprint
Pan, F., Yu, S.-X., Wang, X., Huang, H.-C., Cai, Z.-Y., Wang, J., Lin, S.-Y., Gao, Y.-L., Li, E., & Xu, L. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.05.471340 · Cited by 2
“Considering this, we next removed common PMD regions using published annotations[18] and repeated the unsupervised”
BackgroundMethodGull, N., Jones, M., Peng, P.-C., Coetzee, S. G., Silva, T. A., Plummer, J., Reyes, A., Davis, B. D., Chen, S., Lawrenson, K., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1214611/v1 · Cited by 2
Self-citationEvaluating The Infinium Human MethylationEPIC v2 BeadChipPreprint
Kaur, D., Lee, S., Goldberg, D., Spix, N. J., Hinoue, T., Li, H., Dwaraka, V. B., Smith, R. C., Shen, H., Liang, G., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-2781268/v1 · Cited by 2
Self-citationMultiomics analysis of narcolepsy T cells: global hypomethylation linked to T cell proliferationPreprint
Shimada, M., Honda, M., Honda, Y., Kodama, T., Hitomi, Y., Tokunaga, K., & Miyagawa, T. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.01.592019 · Cited by 2
Copy number-independent allelic imbalance in mRNA is selected in cancer and has prognostic relevancePreprint
Palou-Márquez, G., Pericot-Masdevall, P., & Supek, F. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.07.611780 · Cited by 3
Tiedemann, R. L., Liang, G., & Jones, P. A. (2022) · Springer eBooks · doi:10.1007/978-3-030-94475-9_1 · Cited by 1
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Interrogating subclonal heterogeneity of liver cancer with single-cell multi-omics analysis
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“These findings align with previous studies that hypomethylated regions in cancer cells are typically gene-sparse and enriched for heterochromatin markers 18 .”
Qian, Y., Lin, R., Liu, Z., Zhang, X., Lin, D., & Su, M. (2025) · Clinical Epigenetics · doi:10.1186/s13148-025-02035-3 · Cited by 1
“To analysis of the distribution of DMPs, we obtained partial methylation domain (PMD) methylation levels from the dataset published by Zhou et al. [20] ( h t t p s : / / z w d z w d . g i t h u b . i o / p m d ) .”
Saskova, K., Landfors, M., Hlaváč, V., Šeborová, K., Brůha, J., Honkova, K., Tomášová, K., Selvi, S., Drábová, J., Hackenhaar, F. S., et al. (2026) · Mutagenesis · doi:10.1093/mutage/geag010 · Cited by 1
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“Genomic annotations of highly methylated domains (HMDs) and partially methylated domains (PMDs) were as described by Zhou et al. [ 31 ].”
A progeria syndrome links DNA hypermethylation to age-related pathology
Sarni, D., Neary, G., Carroll, P. L., Vink, C. S., Billard, C. V., Isobe, T., Weng, X., Portman, J. R., McCartney, D. L., Heyn, P., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02633-8 · Cited by 2
“As DMR analysis is based on close proximity of methylated CpGs, widely dispersed hypomethylation in CpG poor regions characteristic of aging 41 might be overlooked.”
Jang, H., Holmberg, J. C., Nicholson, J. S., Shannon, F., Cerino, E. S., Chai, H. W., Charles, S. T., & Almeida, D. M. (2026) · The Journals of Gerontology Series A · doi:10.1093/gerona/glag202 · Cited by 1
“Precise DNA methylation processes are required for normal mammalian development and influence key processes such as genomic imprinting, carcinogenesis, 19 and aging.”
Salas, L. A., Stewart, T. G., Mobley, B. C., Peng, C., Liu, J., Loganathan, S. N., Wang, J., Ma, Y., Berger, M. S., Absher, D., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-21-0088 · Cited by 1
“Thus, they proposed a remethylation window model, where replication late in the S-phase provides less time for remethylation of newly synthesized daughter strands during DNA replication, contributing to hypomethylation during tumor growth (12).”
BackgroundInfluentialThe emerging field of opportunities for single-cell DNA methylation studies in hematology and beyond
Albinati, L., Bianchi, A., & Beekman, R. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1286716 · Cited by 1
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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