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.