Dynamic antagonism between key repressive pathways maintains the placental epigenome (RRBS)

DNA and Histone-3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb Repressive Complexes regulate the CpG-rich promoters of developmental genes. In contrast to this general framework, the extraembryonic lineages display noncanonical, globally intermediate DNA methylation levels that includes disruption of local Polycomb domains. To better understand this unusual landscape’s molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse Trophoblast Stem Cells (TSCs). We find that the extraembryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized appearance, our data point to a highly controlled equilibrium between counteracting repressors within extraembryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation. Profiling of DNA methylation in trophoblast stem cells in normal conditions and treated with DNMT1 or EZH2 inhibitor.

DNA与组蛋白H3赖氨酸27甲基化（Histone-3 Lysine 27 methylation）通常作为抑制性修饰，在不同的基因组区室中发挥调控功能。在哺乳动物中，绝大多数基因组维持DNA甲基化状态，而多梳抑制复合体（Polycomb Repressive Complexes）负责调控发育基因的富含CpG的启动子区域。与这一通用调控框架不同，胚外谱系呈现出非经典的、整体处于中等水平的DNA甲基化模式，且伴随局部多梳结构域的破坏。为更好解析这一异常表观基因组的分子特性，我们在小鼠滋养层干细胞（Trophoblast Stem Cells，TSCs）中通过遗传与化学手段扰动了主要表观遗传通路。研究发现，胚外表观组反映了持续且动态的从头甲基转移酶（de novo methyltransferase）招募过程，而多梳复合体持续对其进行拮抗，以维持中等水平且局部紊乱的甲基化状态。尽管表观状态看似杂乱无章，我们的数据表明，胚外细胞内相互拮抗的抑制因子之间存在高度受控的平衡——该平衡可无限期维持，且不具备胚胎型表观调控中常见的双稳态特征。本数据集涵盖正常培养条件下，以及经DNA甲基转移酶1（DNMT1）或zeste基因增强子同源物2（EZH2）抑制剂处理的滋养层干细胞的DNA甲基化谱分析数据。