Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. Here, we describe a recently evolved pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation. TET activity is required, albeit indirectly, for global demethylation, which mostly occurs at sites devoid of TET binding. Instead, TET-mediated active demethylation is locus-specific and necessary for activating a subset of genes, including the naïve pluripotency and germline marker Dppa3 (Stella, Pgc7). DPPA3 in turn drives large-scale passive demethylation by directly binding and displacing UHRF1 from chromatin, thereby inhibiting maintenance DNA methylation. Although unique to mammals, we show that DPPA3 alone is capable of inducing global DNA demethylation in non-mammalian species (Xenopus and medaka) despite their evolutionary divergence from mammals more than 300 million years ago. Our findings suggest that the evolution of Dppa3 facilitated the emergence of global DNA demethylation in mammals.

全基因组 DNA 去甲基化是哺乳动物发育和幼稚多能干细胞的独特特征。在这里，我们描述了最近进化的途径，其中通过主动和被动去甲基化的耦合来实现整体低甲基化。 TET 活性是全局去甲基化所必需的，尽管是间接的，而全局去甲基化主要发生在没有 TET 结合的位点。相反，TET 介导的主动去甲基化是位点特异性的，并且是激活基因子集所必需的，包括幼稚多能性和种系标记Dppa3 （ Stella、Pgc7 ）。 DPPA3 反过来通过直接结合 UHRF1 并从染色质上取代 UHRF1 来驱动大规模被动去甲基化，从而抑制 DNA 甲基化的维持。尽管DPPA3是哺乳动物所特有的，但我们发现，尽管非哺乳动物物种（爪蟾和青鳉）在进化上与哺乳动物存在3亿多年前的分歧，但DPPA3单独能够诱导非哺乳动物物种（爪蟾和青鳉）的整体DNA去甲基化。我们的研究结果表明， Dppa3的进化促进了哺乳动物中整体 DNA 去甲基化的出现。