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  Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer

Smith, Z. D., Shi, J., Gu, H., Donaghey, J., Clement, K., Cacchiarelli, D., et al. (2017). Epigenetic restriction of extraembryonic lineages mirrors the somatic transition to cancer. Nature, 549(7673), 543-547. doi:10.1038/nature23891.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-FFA9-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-FFAA-9
Genre: Journal Article

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 Creators:
Smith, Zachary D. , Author
Shi, Jiantao, Author
Gu, Hongcang, Author
Donaghey, Julie , Author
Clement, Kendell , Author
Cacchiarelli, Davide , Author
Gnirke, Andreas , Author
Michor, Franziska , Author
Meissner, Alexander1, Author              
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              

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Free keywords: DNA methylation, Cancer epigenetics, Embryogenesis
 Abstract: In mammals, the canonical somatic DNA methylation landscape is established upon specification of the embryo proper and subsequently disrupted within many cancer types1–4. However, the underlying mechanisms that direct this genome-scale transformation remain elusive, with no clear model for its systematic acquisition or potential developmental utility5,6. 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 progenitor7,8. 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 types9. 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 cues10. 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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Language(s): eng - English
 Dates: 2017-08-032017-09-202017-09-28
 Publication Status: Published in print
 Pages: 5
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/nature23891
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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 549 (7673) Sequence Number: - Start / End Page: 543 - 547 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238