Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Human Biology and BioImaging, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Nat Commun. 2020 Nov 24;11(1):5972. doi: 10.1038/s41467-020-19603-1.
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.
基因组范围的 DNA 去甲基化是哺乳动物发育和原始多能干细胞的独特特征。在这里，我们描述了一个最近进化出的途径，其中通过主动和被动去甲基化的偶联来实现全局去甲基化。TET 活性是必需的，尽管是间接的，对于全局去甲基化，这主要发生在没有 TET 结合的位点。相反，TET 介导的主动去甲基化是局部的，对于激活包括原始多能性和生殖系标记物 Dppa3（Stella，Pgc7）在内的一组基因是必要的。DPPA3 反过来通过直接结合并将 UHRF1 从染色质上置换出来，从而抑制维持性 DNA 甲基化，从而驱动大规模的被动去甲基化。尽管这是哺乳动物所特有的，但我们表明，尽管 DPPA3 与哺乳动物的进化分歧超过 3 亿年，但它能够在非哺乳动物物种（非洲爪蟾和斑马鱼）中诱导全局 DNA 去甲基化。我们的发现表明，Dppa3 的进化促进了哺乳动物中全局 DNA 去甲基化的出现。
