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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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“Previously studies suggested that PMD hypomethylation accumulation in cancer mainly drive by mitotic cell division, despite strong expression of the DNA methylation maintenance machinery (63).”
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Comprehensive evaluation of the Infinium human MethylationEPIC v2 BeadChip
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“Knowledge of the genome-wide cytosine modification profile reveals cell identity [4], cell pathological state [5] and mitotic history [6] and holds therapeutic and diagnostic promises in medicine [7].”
BackgroundSelf-citationBack to the Colorectal Cancer Consensus Molecular Subtype Future
Menter, D. G., Davis, J. S., Broom, B. M., Overman, M. J., Morris, J. S., & Kopetz, S. (2019) · Current Gastroenterology Reports · doi:10.1007/s11894-019-0674-9 · Cited by 88
TET methylcytosine oxidases: new insights from a decade of research
Lio, C. J., Yue, X., López-Moyado, I. F., Tahiliani, M., Aravind, L., & Rao, A. (2020) · Journal of Biosciences · doi:10.1007/s12038-019-9973-4 · Cited by 80
“It is well known that cancer genomes display DNA hypomethylation which covers long regions of the genome and overlaps with lamina-associated domains, H3K9me2/3-marked, late-replicating regions of the genome (Berman et al. 2011; Hon et al. 2012; Zhou et al. 2018).”
BackgroundThe immune factors driving DNA methylation variation in human blood
Bergstedt, J., Azzou, S. A. K., Tsuo, K., Jaquaniello, A., Urrutia, A., Rotival, M., Lin, D. T. S., MacIsaac, J. L., Kobor, M. S., Albert, M. L., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33511-6 · Cited by 82
Evaluation of whole-genome DNA methylation sequencing library preparation protocols
Morrison, J., Koeman, J. M., Johnson, B. K., Foy, K. K., Beddows, I., Zhou, W., Chesla, D. W., Rossell, L. L., Siegwald, E. J., Adams, M., et al. (2021) · Epigenetics & Chromatin · doi:10.1186/s13072-021-00401-y · Cited by 79
Self-citationDNA Methylation in Epidermal Differentiation, Aging, and Cancer
Köhler, F., & Rodríguez‐Paredes, M. (2019) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2019.05.011 · Cited by 80
“Hence, keratinocyte differentiation cannot begin in the basal layer in the absence of the master regulator p63 (Soares and Zhou, 2018) or end in the granular layer without the finely tuned expression of the epidermal differentiation complex, a group of about 60 genes clustered in a 2 Mb region on…”
BackgroundInfluentialDNA hypomethylation silences anti-tumor immune genes in early prostate cancer and CTCs
Guo, H., Vuille, J. A., Wittner, B. S., Lachtara, E. M., Hou, Y., Lin, M., Zhao, T., Raman, A. T., Russell, H. C., Reeves, B. A., et al. (2023) · Cell · doi:10.1016/j.cell.2023.05.028 · Cited by 83
“Conflicting models have suggested that hypomethylated blocks are either a direct consequence of cell transformation(14) or an incidental result of excessive cell proliferation.(13,15) The functional consequences of hypomethylationassociated gene silencing and potential selection pressures that shape such domains are n…”
Brinkman, A. B., Nik‐Zainal, S., Simmer, F., Rodríguez-González, F. G., Smid, M., Alexandrov, L. B., Butler, A. P., Martin, S., Davies, H. R., Głodzik, D., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09828-0 · Cited by 76
Lamina Associated Domains and Gene Regulation in Development and Cancer
Lochs, S. J. A., Kefalopoulou, S., & Kind, J. (2019) · Cells · doi:10.3390/cells8030271 · Cited by 75
“Noteworthy is a recent study shedding light upon the occurrence of genome-wide 5mC depletion [84].”
BackgroundEpigenetic deregulation of lamina-associated domains in Hutchinson-Gilford progeria syndrome
Köhler, F., Bormann, F., Raddatz, G., Gutekunst, J., Corless, S., Musch, T., Lonsdorf, A. S., Erhardt, S., Lyko, F., & Rodríguez‐Paredes, M. (2020) · Genome Medicine · doi:10.1186/s13073-020-00749-y · Cited by 77
Quantifying the stochastic component of epigenetic aging
Tong, H., Dwaraka, V. B., Chen, Q., Luo, Q., Lasky-Su, J. A., Smith, R., & Teschendorff, A. E. (2024) · Nature Aging · doi:10.1038/s43587-024-00600-8 · Cited by 83
“It is widely known that a substantial component of age-associated DNAm changes in mitotic tissues is associated with cell division 32,45–47 , 55– 57 .”
DNA methylation profiling as a model for discovery and precision diagnostics in neuro-oncology
Pratt, D. W., Sahm, F., & Aldape, K. (2021) · Neuro-Oncology · doi:10.1093/neuonc/noab143 · Cited by 76
Characterizing DNA methylation signatures of retinoblastoma using aqueous humor liquid biopsy
Li, H., Xu, L., Weisenberger, D. J., Li, M., Zhou, W., Peng, C., Stachelek, K., Cobrinik, D. E., Liang, G., & Berry, J. L. (2022) · Nature Communications · doi:10.1038/s41467-022-33248-2 · Cited by 70
Self-citationZou, Q., Wang, X.-L., Ren, D., Hu, B., Tang, G.-N., Zhang, Y., Huang, M.-J., Pai, R., Buchanan, D., Win, A., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-002671 · Cited by 60
“…tissues and cells, including CRC tissue (n=45) and adjacent normal tissue (n=44), normal (NCM460) and cancerous (RKO, SW48, HCT8, and HCT15) colon epithelial cell lines and multiple immune cells (CD4 + T cells, monocytes, and B cells), which represented the major components of CRC tissues.”
The impact of DNA methylation on CTCF-mediated 3D genome organization
Monteagudo, A., Noordermeer, D., & Greenberg, M. (2024) · Nature Structural & Molecular Biology · doi:10.1038/s41594-024-01241-6 · Cited by 70
“Although DNA methylation is weakly associated with lamina-associated domains (LADs) 94 , there is evidence that DNA methylation misregulation is correlated with LAD reorganization in aging and cancer 95 .”
A hyper-quiescent chromatin state formed during aging is reversed by regeneration
Yang, N., Occean, J. R., Melters, D. P., Shi, C., Wang, L., Stransky, S., Doyle, M. E., Cui, C., Delannoy, M. R., Fan, J., et al. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.04.005 · Cited by 73
Translational efficiency across healthy and tumor tissues is proliferation‐related
Hernandez‐Alias, X., Benisty, H., Schaefer, M. H., & Serrano, L. G. (2020) · Molecular Systems Biology · doi:10.15252/msb.20199275 · Cited by 66
“As 1500TSS methylation of tRNA genes lead to an average coverage of only 37% genes, 505 we also analyzed the recently published bisulfite sequencing data of 47 samples across nine 506 cancer types (Table S3) (39).”
BackgroundMethodPRC2-AgeIndex as a universal biomarker of aging and rejuvenation
Moqri, M., Cipriano, A., Simpson, D. J., Rasouli, S., Murty, T., de Jong, T. A., Nachun, D. C., Brandine, G. D. S., Ying, K., Tarkhov, A. E., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-50098-2 · Cited by 70
“Given the correlation of cell replication and the loss of DNA methylation 10 , the effect of prolonged cell replication in fully differentiated cells on DNAm gain within high-PRC2 LMRs was assessed using WGBS data from healthy and cancer samples from 8 different cancer types from The Cancer Genome…”
BackgroundMethodSelf-citationCell-Free DNA-Methylation-Based Methods and Applications in Oncology
Galardi, F., Luca, F. D., Romagnoli, D., Biagioni, C., Moretti, E., Biganzoli, L., Leo, A. D., Migliaccio, I., Malorni, L., & Benelli, M. (2020) · Biomolecules · doi:10.3390/biom10121677 · Cited by 69
“Whole genome sequencing WGBS 10 ng full methylome DNA degradation; requires high sequencing depth; low input DNA may induce PCR bias ••••• [51,53,54,56]”
BackgroundMethodLu, J., Cannizzaro, E., Meier‐Abt, F., Scheinost, S., Bruch, P., Giles, H. A. R., Luetge, A., Hüllein, J., Wagner, L., Giacopelli, B., et al. (2021) · Nature Cancer · doi:10.1038/s43018-021-00216-6 · Cited by 62
Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas
Li, Y., Goldberg, E. M., Chen, X., Xu, X., McGuire, J. T., Leuzzi, G., Karagiannis, D., Tate, T., Farhangdoost, N., Horth, C., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.09.007 · Cited by 65
Mother–child transmission of epigenetic information by tunable polymorphic imprinting
Carpenter, B. L., Zhou, W., Madaj, Z., DeWitt, A. K., Ross, J. P., Grønbæk, K., Liang, G., Clark, S. J., Molloy, P. L., & Jones, P. A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815005115 · Cited by 56
“This analysis was also performed on matched normal tissues from the TCGA database, as shown in SI Appendix, Fig.”
ResultSelf-citationClock Work: Deconstructing the Epigenetic Clock Signals in Aging, Disease, and ReprogrammingPreprint
Levine, M. E., Higgins‐Chen, A., Thrush, K., Minteer, C. J., & Niimi, P. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.02.13.480245 · Cited by 60
“HypoClock is another measure initially derived to track mitotic rates across cells and tissues 32 .”
BackgroundInfluentialChen, M., Fu, R., Chen, Y., Li, L., & Wang, S. (2025) · Nature Methods · doi:10.1038/s41592-024-02567-1 · Cited by 56
Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myelomaPreprint
Ciriza, R. O., Kulis, M., Russiñol, N., Chapaprieta, V., Carrasco‐Leon, A., García-Torre, B., Charalampopoulou, S., Clot, G., Beekman, R., Meydan, C., et al. (2020) · Genome Research · doi:10.1101/gr.265520.120 · Cited by 54
“This phenomenon of DNA hypomethylation in repressed, late-replicating regions has been recently linked to mitotic cell division rather than to a regulatory function (Zhou et al. 2018).”
Mechanisms of DNA Methylation Regulatory Function and Crosstalk with Histone Lysine Methylation
Tibben, B. M., & Rothbart, S. B. (2023) · Journal of Molecular Biology · doi:10.1016/j.jmb.2023.168394 · Cited by 61
Nardini, C., Moreau, J., Gensous, N., Ravaioli, F., Garagnani, P., & Bacalini, M. G. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.10.009 · Cited by 54
Desaulniers, D. M., Vasseur, P., Jacobs, A. C., Aguila, M. C., Ertych, N., & Jacobs, M. N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222010969 · Cited by 55
Acute lymphoblastic leukemia displays a distinct highly methylated genome
Hetzel, S., Mattei, A. L., Kretzmer, H., Qu, C., Chen, X. '., Fan, Y., Wu, G., Roberts, K. G., Luger, S. M., Litzow, M. R., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00370-5 · Cited by 52
Rodríguez‐Ubreva, J., Arutyunyan, A., Bonder, M. J., Molina, L. D. P., Clark, S. J., de la Calle‐Fabregat, C., García‐Alonso, L., Handfield, L., Ciudad, L., Andrés‐León, E., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29450-x · Cited by 59
Joo, J. E., Clendenning, M., Wong, E. M., Rosty, C., Mahmood, K., Georgeson, P., Winship, I., Preston, S., Win, A. K., Dugué, P., et al. (2021) · Cancers · doi:10.3390/cancers13112589 · Cited by 50
“Furthermore, DNAm is shown to be an accurate molecular indicator for biological age and this has led to the development of numerous tools for estimating biological age using genome-wide DNAm data (16-22).”
MethodProtein Interactions at Oxidized 5-Methylcytosine Bases
Pfeifer, G. P., Szabó, P. E., & Song, J. (2019) · Journal of Molecular Biology · doi:10.1016/j.jmb.2019.07.039 · Cited by 49
“However, there are circumstances where methylation patterns may deteriorate (such as during aging or carcinogenesis), often involving slowly operating processes that enable a progressive loss of methylation over time [14] or that facilitate encroachment of methylation into previously unmethylated CpG islands [15].”
BackgroundLutsik, P., Baude, A., Mancarella, D., Öz, S., Kühn, A., Tóth, R., Hey, J., Toprak, U. H., Lim, J., Nguyễn, V. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18955-y · Cited by 49
“The majority of regions (predominantly LMDs III and IV) matched the criteria for partially methylated domains i.e., megabase-scale domains of predominantly repressive chromatin with low gene density 22 .”
Epigenetic regulation of bone remodeling and bone metastasis
Sharma, G., Sultana, A., Abdullah, K. M., Pothuraju, R., Nasser, M. W., Batra, S. K., & Siddiqui, J. A. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.11.002 · Cited by 49
Dmitrijeva, M., Ossowski, S., Serrano, L. G., & Schaefer, M. H. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky498 · Cited by 54
“Finally, hypomethylation has been shown to affect long stretches of the genome which coincide with LADs and late-replicating regions (16,103).”
BackgroundMeunier, L., Hirsch, T. Z., Caruso, S., Imbeaud, S., Bayard, Q., Roehrig, A., Couchy, G., Nault, J., Llovet, J. M., Blanc, J., et al. (2021) · Hepatology · doi:10.1002/hep.31796 · Cited by 52
“The DNA methylation landscape of human cancers is modulated by various factors, including the cell of origin, (15) age-related processes, (16,17) environmental exposures, (18) driver alterations, (19) deregulated oncogenic pathways, (20) and stromal cell composition.”
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Aging and cancer epigenetics: Where do the paths fork?
Pérez, R. F., Tejedor, J. R., Fernández, A. F., & Fraga, M. F. (2022) · Aging Cell · doi:10.1111/acel.13709 · Cited by 44
Biologically informed deep learning for explainable epigenetic clocks
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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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