The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.
Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer
Open accessAbstract
In mammals, the canonical somatic DNA methylation landscape is established upon specification of the embryo proper and subsequently disrupted within many cancer types. However, the underlying mechanisms that direct this genome-scale transformation remain elusive, with no clear model for its systematic acquisition or potential developmental utility. Here, we analysed global remethylation from the mouse preimplantation embryo into the early epiblast and extraembryonic ectoderm. We show that these two states acquire highly divergent genomic distributions with substantial disruption of bimodal, CpG density-dependent methylation in the placental progenitor. The extraembryonic epigenome includes specific de novo methylation at hundreds of embryonically protected CpG island promoters, particularly those that are associated with key developmental regulators and are orthologously methylated across most human cancer types. Our data suggest that the evolutionary innovation of extraembryonic tissues may have required co-option of DNA methylation-based suppression as an alternative to regulation by Polycomb-group proteins, which coordinate embryonic germ-layer formation in response to extraembryonic cues. Moreover, we establish that this decision is made deterministically, downstream of promiscuously used-and frequently oncogenic-signalling pathways, via a novel combination of epigenetic cofactors. Methylation of developmental gene promoters during tumorigenesis may therefore reflect the misappropriation of an innate trajectory and the spontaneous reacquisition of a latent, developmentally encoded epigenetic landscape.
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“The similarity between tumor and placenta methylomes suggests that tumorigenesis may represent a latent developmental epigenomic program.”
From Dynamic DNA methylation: In the right place at the right time (2018) · cites this paper as [46]
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Cites
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Integrative analysis of 111 reference human epigenomes
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Self-citationFull-length RNA-seq from single cells using Smart-seq2
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CpG islands and the regulation of transcription
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DNA methylation: roles in mammalian development
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Lea, G., Gu, Y., Xiong, F., & Hanna, C. W. (2026) · BMC Genomics · doi:10.1186/s12864-026-13123-w
Lu, T., Li, Y., Wen, Y., Xu, Z., Lin, H., Shao, G., & Li, X. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113554
Folate deficiency disrupts key metabolic transitions within the developing neural ectodermPreprint
Dias, N., Lewinsohn, D. P., Colgan, W. N., Wang, M., Kijima, Y., Villagrana, J., Hou, T.-C. J., Gowri, G., Chau, A., Aktaş, T., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.18.752622
Self-citationDNA methylation maintenance at heterochromatin
Wassing, I. E., & Funabiki, H. (2026) · DNA repair · doi:10.1016/j.dnarep.2026.103965
Epigenetic regulators partition the genome by evolutionary and developmental constraintPreprint
Kijima, Y., Villagrana, J., Wang, M., Tornisiello, R., Dias, N., Hou, T.-C. J., Tse, K. Y., Wang, J., Kretzmer, H., Sumigray, K., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.01.755350 · Cited by 1
Self-citationLiu, F., Huang, J., Zheng, Y., Fu, L., Wu, X., Zhao, N., Wang, Y., Gnirke, A., Meissner, A., Wang, X., et al. (2026) · Nature Protocols · doi:10.1038/s41596-026-01452-9
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Metadata
- Authors
- Smith, Z. D., Shi, J., Gu, H., Donaghey, J., Clement, K., Cacchiarelli, D., Gnirke, A., Michor, F., & Meissner, A.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Meissner, Alexander
- ORCID
- Venue
- Nature
- Published
- 2017-09-20
- Volume
- 549
- Issue
- 7673
- Pages
- 543-547
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5789792
- OpenAlex
- W2754109996
- Cited by
- 201
- References
- 67
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 20 · 2023: 20 · 2022: 29 · 2021: 37 · 2020: 26 · 2019: 25 · 2018: 11 · 2017: 3
- FWCI
- 7.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- New York Stem Cell Foundation (P01GM099117, R01DA036898)
- Starr Foundation (R01DA036898)
- Israel Science Foundation
- Max-Planck-Gesellschaft
- National Institutes of Health (5rm1hg006193-10, NIH U54CA193461)
- National Institute on Drug Abuse (R01DA036898)
- National Human Genome Research Institute (RM1‐HG006193, P50HG006193)
- National Cancer Institute (U54CA193461)
- National Institute of General Medical Sciences (P01GM099117)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD078679)
- 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, extraembryonic ectoderm, epiblast, preimplantation embryo, de novo methylation, CpG island promoters, developmental regulators, cancer epigenetics, Polycomb group proteins, mouse embryo development, carcinogenesis
- MeSH terms
- Animals, Blastocyst, Ectoderm, Female, Germ Layers, Humans, Male, Neoplasms, Placenta, Pregnancy, Promoter Regions, Genetic, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Developmental, CpG Islands, Cell Lineage, DNA Methylation, Epigenesis, Genetic, Mice
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