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DPPA2 and DPPA4 are necessary to establish a 2C-like state in mouse embryonic stem cells. De Iaco A et al. (2019) 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.//////////////////
Dppa2 and Dppa4 are Closely Linked SAP Motif Genes Restricted to Pluripotent Cells and the Germ Line. Maldonado-Saldivia J et al. Despite the enormous medical potential of embryonic stem (ES) cells, the molecular mechanisms conferring the ability to differentiate into all cell types of the embryo remain elusive. We used an in silico approach to identify genes expressed exclusively in mouse pre-implantation embryos and pluripotent cell lines. Two of these genes were Dppa2 (developmental pluripotency associated gene2); and Dppa4 (developmental pluripotency associated gene4), which we show are closely linked genes encoding putative nuclear SAP-domain proteins expressed in human and mouse pluripotent stem cells and germ cell tumour derived EC cells. In the mouse, these genes are transcribed in GV stage oocytes and throughout the cleavage stages of embryogenesis. They then become restricted to the pluripotent inner cell mass (ICM) of blastocysts and are subsequently down regulated. Post gastrulation, Dppa2 and Dppa4 are expressed only in the developing germ line, showing that these genes mark cells of the pluripotent cycle. In the germ line, both genes are down regulated as the germ cells commit to the oogenic pathway or soon after commitment to the spermatogenic pathway. We have observed similar germ line expression profiles for other pluripotent markers, and these results are consistent with the hypothesis that pluripotent markers must be downregulated during foetal germ line development, a process that may be required to facilitate appropriate germ line differentiation. The study of expression and function of pluripotent markers such as Dppa2 and Dppa4 is likely to unveil new aspects in the regulation of pluripotency and germ line development in mammals.
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