Epigenetic restriction of embryonic and extraembryonic lineages mirrors the somatic transition to cancer (RNA-seq)

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. Comparison of gene expression patterns in Extraembryonic Ectoderm and cancer数十年来的协同研究已让学界对经典体细胞DNA甲基化（DNA methylation）图谱，以及其在多数人类癌症中的系统性失调机制形成了全面认知。然而，驱动这一全基因组范围重塑的底层机制仍未阐明，目前既缺乏明确的发生模型，也未明确其潜在的发育功能意义。本研究针对植入前胚胎从低甲基化状态向早期上胚层与胚外外胚层（extraembryonic ectoderm）的全局重新甲基化过程，开展了碱基对分辨率级别的分析。研究结果显示，这两种细胞状态呈现出截然不同的基因组分布特征：近端上胚层形成了体细胞中常见的、依赖CpG密度的经典甲基化模式，而胚外表观基因组则呈现出显著更高的镶嵌性。此外，该异常甲基化模式包含数百个携带CpG岛启动子的基因的特异性从头甲基化，这些基因在早期胚胎发育中发挥功能，且在大规模人类癌症队列中均存在同源基因的甲基化现象。基于上述数据，本研究提出了一个模型：真兽类哺乳动物中胚外组织的演化创新，需要将基于DNA甲基化的基因沉默作为替代通路，替代胚胎发育中所利用的多梳蛋白家族（Polycomb group proteins）——后者通常在原肠胚形成初期响应胚外信号，以协调胚层形成过程。此外，本研究证实，这一细胞命运决定过程确定性地发生在广泛激活且常具有致癌性的成纤维细胞生长因子信号通路（FGF signaling pathway）的下游，并依赖于一套全新的表观遗传辅因子组合。因此，癌症发生过程中该沉默机制被招募至发育基因的现象，实则是先天调控通路被误用的结果——这类通路可能在体细胞中自发切换为一种替代性表观图谱。对胚外外胚层与癌症样本的基因表达模式进行对比。