DPPA2 and DPPA4 are necessary to establish a 2C‐like state in mouse embryonic stem cells

After fertilization of the transcriptionally silent oocyte, expression from both parental chromosomes is launched through zygotic genome activation (ZGA), occurring in the mouse at the 2‐cell (2C) stage. Among the first elements to be transcribed are the Dux gene, the product of which induces a wide array of ZGA genes, and a subset of evolutionary recent LINE‐1 retrotransposons that regulate chromatin accessibility in the early embryo. The maternally inherited factors that activate Dux and LINE‐1 transcription have so far remained unknown. Mouse embryonic stem cells (mESCs) recapitulate some aspects of ZGA in culture, owing to their ability to cycle through a 2C‐like stage when Dux , its target genes, and LINE‐1 integrants are expressed. Here, we identify the paralog proteins DPPA2 and DPPA4 as necessary for the activation of Dux and LINE‐1 expression in mESCs. Since their encoding RNAs are maternally transmitted to the zygote, it is likely that these factors are important upstream mediators of murine ZGA. Synopsis DPPA2 and DPPA4 promote Dux and LINE‐1 expression in mESCs, generating a transcriptional program similar to zygotic genome activation. DPPA2/4 are maternally expressed genes present at fertilization. DPPA2/4 regulate expression of Dux in mESCs. DPPA2/4 regulate expression of young LINE‐1 elements in mESCs. Graphical Abstract DPPA2 and DPPA4 promote Dux and LINE‐1 expression in mESCs, generating a transcriptional program similar to zygotic genome activation.