GSE98963
Epigenetic restriction of embryonic and extraembryonic lineages mirrors the somatic transition to cancer (Perturbation-RRBS)
Concerted efforts over past decades have established a thorough understanding of the canonical somatic DNA methylation landscape as well as its systematic misregulation across most human cancers.  However, the underlying mechanism that directs this genome-scale transformation remains elusive, with no clear model for its acquisition or understanding of its potential developmental utility. Here we present base pair resolution analysis of global remethylation from the hypomethylated state of the preimplantation embryo into the early epiblast and extraembryonic ectoderm. We show that these two states acquire highly divergent genomic distributions: while the proximal epiblast establishes a canonical CpG-density dependent pattern found in somatic cells, the extraembryonic epigenome becomes substantially more mosaic.  Moreover, this alternate pattern includes specific de novo methylation of hundreds of CpG island promoter containing genes that function in early embryonic development and are orthologously methylated across an extensive cohort of human cancers.  From these data, we propose a model where the evolutionary innovation of extraembryonic tissues in eutherian mammals required cooption of DNA methylation-based suppression as an alternate pathway to the embryonically utilized Polycomb group proteins, which otherwise coordinate germ layer formation in response to extraembryonic cues at the onset of gastrulation.  Moreover, we establish that this decision is made deterministically downstream of the promiscuously utilized, and frequently oncogenic, FGF signaling pathway and utilizes a novel combination of epigenetic cofactors.  Recruitment of this silencing mechanism to developmental genes during cancer therefore reflects the misappropriation of an innate regulatory pathway that may be spontaneously sampled as an alternate epigenetic landscape within somatic cells. Overall design: Comparison of DNA methylation patterns in Extraembryonic Ectoderm and cancer