Dppa2/4 promotes zygotic genome activation by binding to GC-rich region in signaling pathways

Abstract

9Developmental pluripotency associated 2 (Dppa2) and Dppa4 as positive drivers 10 were helpful for transcriptional regulation of ZGA, but it remains poorly understood 11 how these two factors regulate the zygotic transcriptional program. Here, we 12 systematically assessed the cooperative interplay between Dppa2 and Dppa4 in 13 regulating cell pluripotency of three cell types and found that simultaneous 14 overexpression of Dppa2/4 can make induced pluripotent stem cells (IPSCs) closer to 15 embryonic stem cells (ESCs). Motif occupancy analysis revealed that the repertoire of 16 Dppa2/4 targets depends upon the CG content, in which GC-rich region is the prior 17 binding signatures. Compared with other pluripotency transcription factors (TFs), 18 Dppa2 and 4 tend to bind on proximal promoter (0-500bp), especially GC-rich region 19of proximal promoter. We also found that the target regulation ability of Dppa4 is 20 superior to that of Dppa2 in ESCs, whereas the coordinately binding ability of both 21 was the most substantial. Moreover, there was more potent effect of Dppa2/4 22 regulation on signaling pathways compared with other TFs, in which 75% and 85% 23 signaling pathways were significantly activated by Dppa2 and Dppa4, respectively. 24Notably, Dppa2/4 also can dramatically trigger the decisive signaling pathways 25 associated with developmental reprogramming for facilitating ZGA, including Hippo, 26 MAPK and TGF-beta signaling pathways and so on. At last, we predicted that 27 Alkaline phosphatase, placental-like 2 (Alppl2) was directly regulated by Dppa2 and 28 Dppa4 as a new ZGA regulator. Collectively, our studies show how Dppa2/4 triggers 29 the decisive signaling pathways waves for facilitating ZGA, and Alppl2 was predicted 30 serve as a candidate driver of ZGA to regulate pre-embryonic development.31 32

DPPA2, DPPA4, and other DPPA factor epigenomic functions in cell fate and cancer

“…Further contributing to our knowledge of the role of DPPA2/4 in ZGA, ChIP-seq and RNA-seq studies demonstrate that DPPA2 and DPPA4 bind to and regulate a gene called alkaline phosphatase placental-like 2 (Alppl2), which is upregulated during ZGA and has been shown to have roles in folate metabolism, a pathway that is crucial for ensuring proper DNA methylation among many other cellular functions (Li et al, 2020).…”