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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.