Two waves of de novo methylation during mouse germ cell development. Mus musculus strain:C57BL/6

Multiple waves of de novo methylation occur during mouse germ cell development. Following a genome-wide wave of erasure, mammalian germ cells reprogram their epigenome via de novo DNA methylation to ensure the transcriptional competence of protein-coding genes while silencing retrotransposons and other mobile elements. piRNAs are thought to target methylation over the bulk retrotransposons. Here we show that most retrotransposon silencing is instead achieved via a default, non-selective, wave of de novo methylation. However, we found that a small subset of evolutionary young and potentially active retrotransposons evade this initial wave by mimicking features of protein-coding genes. These elements remain transcriptionally active in developing germ cells and become susceptible to an active secondary wave of piRNA-mediated de novo methylation. Thus, we posit that through these two separate waves, germ cells can acquire at each generation a unique and adaptive epigenome.小鼠生殖细胞发育过程中存在多轮从头DNA甲基化（de novo methylation）事件。在经历全基因组范围的一轮去甲基化浪潮后，哺乳动物生殖细胞通过从头DNA甲基化重编程其表观基因组（epigenome），以保障蛋白编码基因的转录活性，同时沉默逆转录转座子（retrotransposon）与其他移动遗传元件。此前学界认为Piwi互作RNA（Piwi-interacting RNA，piRNA）会靶向绝大多数逆转录转座子的甲基化修饰。本研究表明，绝大多数逆转录转座子的沉默实则通过一次默认的、非选择性的从头DNA甲基化浪潮完成。但我们发现，一小部分进化上较为年轻且具备潜在活性的逆转录转座子，可通过模拟蛋白编码基因的特征逃过这一初始甲基化浪潮。这些元件在发育中的生殖细胞内仍保持转录活性，并会受到第二轮由piRNA介导的主动从头DNA甲基化靶向修饰。据此我们提出，通过这两轮独立的甲基化浪潮，生殖细胞可在每一代中获得独特且具有适应性的表观基因组。