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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Aged cells (and cancer cells) generally lose DNA methylation from gene bodies.
“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]
The Abstract reports methylation loss in cancer and increasing hypomethylation with age, but locates the loss primarily in late-replicating, gene-poor partially methylated domains—not generally in gene bodies. The Results section on replication timing and H3K36me3 reports that CpGs marked by H3K36me3, a mark associated with active gene bodies, remained highly methylated. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOld yeast cells have decreased H3K36me3 levels and increased intragenic transcripts, while DNA methylation decreases with age in humans.
“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]
Analysis of whole-genome methylomes of 39 primary tumors in mouse and human shows pronounced loss of methylation at nuclear lamina-associated partially methylated domains located in late-replicating parts of the genome.
“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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Luo, C., Hajkova, P., & Ecker, J. R. (2018) · Science · doi:10.1126/science.aat6806 · Cited by 668 · see citing works
The UCSC Xena platform for public and private cancer genomics data visualization and interpretationPreprint
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Measuring biological age using omics data
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“Additionally, studies have suggested that alterations in CpG methylation status that selectively alter heterochromatin associations with the nuclear lamina could be a driver of ageing 149,150 .”
BackgroundDNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
Jung, H., Kim, H. S., Kim, J. Y., Sun, J., Ahn, J. S., Ahn, M., Park, K., Esteller, M., Lee, S., & Choi, J. K. (2019) · Nature Communications · doi:10.1038/s41467-019-12159-9 · Cited by 537 · see citing works
SeSAMe: reducing artifactual detection of DNA methylation by Infinium BeadChips in genomic deletions
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“Whole-genome bisulfite sequencing data for 47 samples were also obtained from GDC, with the experimental procedure described in (17).”
MethodSelf-citationA clinically applicable integrative molecular classification of meningiomas
Nassiri, F., Liu, J., Patil, V. S., Mamatjan, Y., Wang, J. Z., Hugh-White, R., Macklin, A. M., Khan, S., Singh, O., Karimi, S., et al. (2021) · Nature · doi:10.1038/s41586-021-03850-3 · Cited by 459 · see citing works
Universal DNA methylation age across mammalian tissues
Lu, A. T.-H., Fei, Z., Haghani, A., Robeck, T. R., Zoller, J. A., Li, C. Z., Lowe, R., Yan, Q. J., Zhang, J., Vu, H., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00462-6 · Cited by 495 · see citing works
“2 × 10 (22) 7 × 10 (40) 1 × 10 (16) 1 × 10 (30) 4 × 10 (25) 8 × 10 (50) 1 × 10 (28) 1 × 10 (48) 7 × 10 (30) 2 × 10 (61)”
The DNA methylation landscape of advanced prostate cancer
Zhao, S. G., Chen, W. S., Li, H., Foye, A., Zhang, M., Sjöström, M., Aggarwal, R. R., Playdle, D., Liao, A., Alumkal, J. J., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0648-8 · Cited by 351 · see citing works
Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer
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“Finally, a recent landmark study demonstrated that DNA hypomethylation in cancer is concentrated at late-replicating domains partially methylated in normal tissues, and are enriched in solo “WCGW” CpG sites [28].”
BackgroundResultInfluentialDNA methylation in mammalian development and disease
Smith, Z. D., Hetzel, S., & Meissner, A. (2024) · Nature Reviews Genetics · doi:10.1038/s41576-024-00760-8 · Cited by 280 · see citing works
“In vivo, megabase-scale partially methylated domains (PMDs) start to emerge during differentiation that show overall high but slightly diminished DNA methylation levels compared with highly methylated domains (HMDs).”
InfluentialThe interplay between DNA and histone methylation: molecular mechanisms and disease implications
Li, Y., Chen, X., & Lu, C. (2021) · The EMBO Reports · doi:10.15252/embr.202051803 · Cited by 223 · see citing works
“Recent evidence suggests that DNA hypomethylation at PMDs is coupled to mitotic cell division (possibly due to ineffective maintenance methylation) and gain of heterochromatic histone marks such as H3K9me3 (DEEP Consortium et al , 2018; Zhou et al , 2018).”
Large-Scale Topological Changes Restrain Malignant Progression in Colorectal Cancer
Johnstone, S. E., Reyes, A., Qi, Y., Adriaens, C., Hegazi, E., Pelka, K., Chen, J. H., Zou, L.-L., Drier, Y., Hecht, V. C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.07.030 · Cited by 189 · see citing works
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Epigenetic ageing clocks: statistical methods and emerging computational challenges
Teschendorff, A. E., & Horvath, S. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-024-00807-w · Cited by 220 · see citing works
“In line with this hypothesis, epigenetic mitotic clocks aimed at predicting mitotic age 34,35,37,55,160 display universal age acceleration in cancer and precancerous lesions, holding promise as cancer-risk prediction tools 37,157,159,160 .”
InfluentialSlieker, R. C., Relton, C. L., Gaunt, T. R., Slagboom, P. E., & Heijmans, B. T. (2018) · Epigenetics & Chromatin · doi:10.1186/s13072-018-0191-3 · Cited by 207 · see citing works
“An explanation for the consistent increase in DMPs near ELOVL2 and other age-related DNA methylation changes could be due to underlying mitotic changes, although this has not been observed in previous studies suggesting other mechanisms driving age-related DNA methylation changes [31, 32].”
Before and After: Comparison of Legacy and Harmonized TCGA Genomic Data Commons’ Data
Gao, G. F., Parker, J. S., Reynolds, S. M., Silva, T. C., Wang, L.-B., Zhou, W., Akbani, R., Bailey, M. H., Balu, S., Berman, B. P., et al. (2019) · Cell Systems · doi:10.1016/j.cels.2019.06.006 · Cited by 180 · see citing works
“…are planned to become the default processing version in a forthcoming GDC data release; and Whole-Genome Bisulfite Sequence data for 47 TCGA samples (Zhou et al., 2018a), which can be used to investigate whole-genome methylation patterns. mRNA Expression TCGA RNA-seq data were generated in a…”
BackgroundInfluentialSelf-citationTwo distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation
Nishiyama, A., Mulholland, C. B., Bultmann, S., Kori, S., Endo, A., Saeki, Y., Qin, W., Trummer, C., Chiba, Y., Yokoyama, H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15006-4 · Cited by 159 · see citing works
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A comparison of epigenetic mitotic-like clocks for cancer risk prediction
Teschendorff, A. E. (2020) · Genome Medicine · doi:10.1186/s13073-020-00752-3 · Cited by 144 · see citing works
A comprehensive epigenome atlas reveals DNA methylation regulating skeletal muscle development
Yang, Y., Fan, X., Yan, J., Chen, M., Zhu, M., Tang, Y., Liu, S., & Tang, Z. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1203 · Cited by 142 · see citing works
“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).”
BackgroundInterplay between chromatin marks in development and disease
Janssen, S. M., & Lorincz, M. C. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00416-x · Cited by 141 · see citing works
Random forest-based modelling to detect biomarkers for prostate cancer progression
Tóth, R., Schiffmann, H., Hube‐Magg, C., Büscheck, F., Höflmayer, D., Weidemann, S. A., Lebok, P., Fraune, C., Minner, S. J. P., Schlomm, T., et al. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0736-8 · Cited by 141 · see citing works
“In tumours, stronger hypomethylation in PMDs was significantly associated with higher genome-wide somatic mutation densities [22], supporting our findings of commonly more loss of methylation in more aggressive PCa compared to the good prognosis group.”
BackgroundResultInfluentialMethylation across the central dogma in health and diseases: new therapeutic strategies
Liu, R., Zhao, E., Yu, H., Yuan, C., Abbas, M. N., & Cui, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01528-y · Cited by 147 · see citing works
Universal DNA methylation age across mammalian tissuesPreprint
Lu, A. T., Fei, Z., Haghani, A., Robeck, T. R., Zoller, J. A., Li, C., Lowe, R., Yan, Q. J., Zhang, J., Vu, H., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.01.18.426733 · Cited by 139 · see citing works
Epigenetic Aging: More Than Just a Clock When It Comes to Cancer
Yu, M., Hazelton, W. D., Luebeck, E. G., & Grady, W. M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0924 · Cited by 137 · see citing works
“Conversely, a pronounced and consistent pattern of DNA methylation loss is observed at lamina-associated, partiallymethylated domains in primary cancer samples, as well as in aged tissue (26,27).”
BackgroundDNA methylation networks underlying mammalian traits
Haghani, A., Li, C. Z., Robeck, T. R., Zhang, J., Lu, A. T., Ablaeva, J., Acosta-Rodríguez, V. A., Adams, D. M., Alagaili, A. N., Almunia, J., et al. (2023) · Science · doi:10.1126/science.abq5693 · Cited by 128 · see citing works
“The common partially methylated domains (commonPMD), solo CpGs (WCGW), and highly methylated domain (HMD) annotations are from (42).”
BackgroundInfluentialSelf-citationParadoxical association of TET loss of function with genome-wide DNA hypomethylation
López-Moyado, I. F., Tsagaratou, A., Yuita, H., Seo, H., Delatte, B., Heinz, S., Benner, C. W., & Rao, A. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1903059116 · Cited by 125 · see citing works
“PMDs have also been documented in CD4 T cells from a 103-y-old individual compared with those from a newborn human (22), suggesting that DNA methylation is also progressively lost in the heterochromatin of cells undergoing sustained longterm proliferation.”
BackgroundKatsman, E., Orlanski, S., Martignano, F., Fox-Fisher, I., Shemer, R., Dor, Y., Zick, A., Eden, A., Petrini, I., Conticello, S. G., et al. (2022) · Genome biology · doi:10.1186/s13059-022-02710-1 · Cited by 127 · see citing works
“We confirmed this using WGBS data from TCGA (29) 172 (Supplementary Figure 7A).”
BackgroundMethodInfluentialSelf-citationHamamoto, R., Komatsu, M., Takasawa, K., Asada, K., & Kaneko, S. (2019) · Biomolecules · doi:10.3390/biom10010062 · Cited by 126 · see citing works
“Moreover, in 2009, the first human genome-wide single-base-resolution DNA methylation map was established by Whole Genome Bisulfite Sequencing (WGBS) [59], which showed the utilization of this technique to investigate the relationship between DNA methylation loci and human phenotypes in both basic and clinical researc…”
BackgroundStaying true to yourself: mechanisms of DNA methylation maintenance in mammals
Petryk, N., Bultmann, S., Bartke, T., & Defossez, P. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa1154 · Cited by 120 · see citing works
“Interestingly, the loss of DNA methylation that occurs during aging and in tumors is more prevalent in late-replicating regions, suggesting that incomplete postreplicative methylation may be at fault (136).”
BackgroundDNA methylation dynamics and dysregulation delineated by high-throughput profiling in the mouse
Zhou, W., Hinoue, T., Barnes, B., Mitchell, O. D., Iqbal, W., Lee, S. M., Foy, K. K., Lee, K., Moyer, E. J., VanderArk, A., et al. (2022) · Cell Genomics · doi:10.1016/j.xgen.2022.100144 · Cited by 115 · see citing works
Self-citationTET Enzymes in the Immune System: From DNA Demethylation to Immunotherapy, Inflammation, and Cancer
López-Moyado, I. F., Ko, M., Hogan, P. G., & Rao, A. (2024) · Annual Review of Immunology · doi:10.1146/annurev-immunol-080223-044610 · Cited by 116 · see citing works
Genome-wide association study of cerebral small vessel disease reveals established and novel loci
Chung, J., Marini, S., Pera, J., Norrving, B., Jiménez-Conde, J., Roquer, J., Fernández‐Cadenas, I., Tirschwell, D., Selim, M. H., Brown, D. L., et al. (2019) · Brain · doi:10.1093/brain/awz233 · Cited by 117 · see citing works
“GTEx Portal and Braineac have been used for eQTL mapping in multiple prior studies (Loh et al., 2018; Maguire et al., 2018; Malik et al., 2018; Zhou et al., 2018).”
Functional mechanisms and abnormalities of the nuclear lamina
Karoutas, A., & Akhtar, A. (2021) · Nature Cell Biology · doi:10.1038/s41556-020-00630-5 · Cited by 116 · see citing works
TETs compete with DNMT3 activity in pluripotent cells at thousands of methylated somatic enhancers
Charlton, J., Jung, E. J., Mattei, A. L., Bailly, N., Liao, J., Martin, E. J., Gießelmann, P., Brändl, B., Stamenova, E. K., Müller, F.-J., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0639-9 · Cited by 107 · see citing works
Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging
Liu, Z., Ji, Q., Ren, J., Yan, P., Wu, Z., Wang, S., Sun, L., Wang, Z., Li, J., Sun, G., et al. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.05.004 · Cited by 109 · see citing works
Liu, Z., Zhang, Y., Shi, C., Zhou, X., Xu, K., Jiao, D., Sun, Z., & Han, X. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-020-02697-y · Cited by 106 · see citing works
Martin-Herranz, D. E., Aref‐Eshghi, E., Bonder, M. J., Stubbs, T. M., Choufani, S., Weksberg, R., Stegle, O., Sadiković, B., Reik, W., & Thornton, J. M. (2019) · Genome biology · doi:10.1186/s13059-019-1753-9 · Cited by 100 · see citing works
“We used the same data from the IMR90 cell line as in [87].”
MethodDu, Q., Bert, S. A., Armstrong, N. J., Caldon, C. E., Song, J. Z., Nair, S., Gould, C. M., Luu, P.-L., Peters, T. J., Khoury, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08302-1 · Cited by 102 · see citing works
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The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome
Duran‐Ferrer, M., Clot, G., Nadeu, F., Beekman, R., Baumann, T., Nordlund, J., Marincevic-Zuniga, Y., Lönnerholm, G., Rivas‐Delgado, A., Martín, S., et al. (2020) · Nature Cancer · doi:10.1038/s43018-020-00131-2 · Cited by 97 · see citing works
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Single-cell analysis of clonal maintenance of transcriptional and epigenetic states in cancer cells
Meir, Z., Mukamel, Z., Chomsky, E., Lifshitz, A., & Tanay, A. (2020) · Nature Genetics · doi:10.1038/s41588-020-0645-y · Cited by 98 · see citing works
Zeng, P., Shao, Z., & Zhou, X. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.05.042 · Cited by 97 · see citing works
“In addition, due to the consequence of global epigenetic remodeling mechanism [155,156], altered DNA methylation may simply represent a passenger event rather than a mediation event.”
BackgroundEpigenetic clocks, aging, and cancer
Johnstone, S. E., Gladyshev, V. N., Aryee, M. J., & Bernstein, B. (2022) · Science · doi:10.1126/science.abn4009 · Cited by 93 · see citing works
Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans
Kaasinen, E., Kuismin, O., Rajamäki, K., Ristolainen, H., Aavikko, M., Kondelin, J., Saarinen, S., Berta, D. G., Katainen, R., Hirvonen, E. A. M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09198-7 · Cited by 92 · see citing works
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“…particularly in the context of WCGW (where W = A or T) without neighboring CpGs (dubbed solo-WCGW), has been suggested to track the accumulation of cell divisions in normal cells and is commonly observed in tissues that have undergone extensive clonal expansion, like cancer (Zhou et al., 2018a).”
Self-citationAdam, S., Anteneh, H., Hornisch, M., Wagner, V., Lu, J., Radde, N. E., Bashtrykov, P., Song, J., & Jeltsch, A. (2020) · Nature Communications · doi:10.1038/s41467-020-17531-8 · Cited by 89 · see citing works
Mancarella, D., & Plass, C. (2021) · Genome Medicine · doi:10.1186/s13073-021-00837-7 · Cited by 91 · see citing works
“DNA hypomethylation of late replicating regions, with only a short time window for methylation of the daughter strand during S-phase, was for example associated to the mitotic age [41].”
BackgroundCell division drives DNA methylation loss in late-replicating domains in primary human cells
Endicott, J. L., Nolte, P. A., Shen, H., & Laird, P. W. (2022) · Nature Communications · doi:10.1038/s41467-022-34268-8 · Cited by 91 · see citing works
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Price, A. J., Collado‐Torres, L., Ivanov, N. A., Xia, W. T., Burke, E. E., Shin, J. H., Tao, R., Ma, L., Jia, Y., Hyde, T. M., et al. (2019) · Genome biology · doi:10.1186/s13059-019-1805-1 · Cited by 85 · see citing works
Genetic and epigenetic dependencies in colorectal cancer development
Parmar, S., & Easwaran, H. (2022) · Gastroenterology report · doi:10.1093/gastro/goac035 · Cited by 86 · see citing works
Nature of epigenetic aging from a single-cell perspective
Tarkhov, A. E., Lindstrom-Vautrin, T., Zhang, S., Ying, K., Moqri, M., Zhang, B., Tyshkovskiy, A., Levy, O., & Gladyshev, V. N. (2024) · Nature Aging · doi:10.1038/s43587-024-00616-0 · Cited by 83 · see citing works
Comprehensive evaluation of the Infinium human MethylationEPIC v2 BeadChip
Kaur, D., Lee, S. M., Goldberg, D., Spix, N. J., Hinoue, T., Li, H., Dwaraka, V. B., Smith, R. C., Shen, H., Liang, G., et al. (2023) · Epigenetics Communications · doi:10.1186/s43682-023-00021-5 · Cited by 86 · see citing works
“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 81 · see citing works
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 78 · see citing works
“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., MacIsaac, J., Kobor, M., Albert, M., et al. (2021) · bioRxiv · doi:10.1038/s41467-022-33511-6 · Cited by 73 · see citing works
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 · see citing works
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 79 · see citing works
“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 80 · see citing works
“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 75 · see citing works
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 76 · see citing works
“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 · see citing works
Quantifying the stochastic component of epigenetic aging
Tong, H., Dwaraka, V. B., Chen, Q., Luo, Q., Lasky-Su, J. A., Smith, R. C., & Teschendorff, A. E. (2024) · Nature Aging · doi:10.1038/s43587-024-00600-8 · Cited by 75 · see citing works
“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 75 · see citing works
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 · see citing works
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 · see citing works
“…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 66 · see citing works
“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 71 · see citing works
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 64 · see citing works
“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 65 · see citing works
“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 · see citing works
“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 64 · see citing works
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 64 · see citing works
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 58 · see citing works
“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 58 · see citing works
“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 · see citing works
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 52 · see citing works
“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 55 · see citing works
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 52 · see citing works
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 54 · see citing works
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 · see citing works
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 52 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“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
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Dmitrijeva, M., Ossowski, S., Serrano, L. G., & Schaefer, M. H. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky498 · Cited by 45 · see citing works
“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 45 · see citing works
“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.”
BackgroundInfluentialShareef, S. J., Bevill, S. M., Raman, A. T., Aryee, M. J., van Galen, P., Hovestadt, V., & Bernstein, B. (2021) · Nature Biotechnology · doi:10.1038/s41587-021-00910-x · Cited by 43 · see citing works
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 · see citing works
Biologically informed deep learning for explainable epigenetic clocks
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- 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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