Abstract
The molecular mechanism controlling the zygotic genome activation (ZGA) in mammals remains poorly understood. The 2-cell (2C)-like cells spontaneously emerging from cultures of mouse embryonic stem cells (ESCs) share some key transcriptional and epigenetic programs with 2C-stage embryos. By studying the transition of ESCs into 2C-like cells, we identified developmental pluripotency associated 2 and 4 (Dppa2/4) as important regulators controlling zygotic transcriptional program through directly up-regulating the expression of double homeobox (Dux). In addition, we found that DPPA2 protein is sumoylated and its activity is negatively regulated by small ubiquitin-like modifier (Sumo) E3 ligase protein inhibitor of activated STAT 4 (PIAS4). PIAS4 is down-regulated during ZGA process and during transitioning of ESCs into 2C-like cells. Depleting Pias4 or overexpressing Dppa2/4 is sufficient to activate 2C-like transcriptional program, whereas depleting Dppa2/4 or forced expression of Pias4 or Sumo2–Dppa2 inhibits 2C-like transcriptional program. Furthermore, ectopic expression of Pias4 or Sumo2–Dppa2 impairs early mouse embryo development. In summary, our study identifies key molecular rivals consisting of transcription factors and a Sumo2 E3 ligase that regulate zygotic transcriptional program upstream of Dux.
Highlights
Zygotic genome activation (ZGA) occurs predominantly at the 2-cell (2C) stage of mouse embryo and 4- to 8-cell stages in human embryo [1,2,3], which is essential for the development control passed from maternal to newly synthesized RNA and proteins
We confirmed that knocking down Sumo2, but not Sumo1, significantly increased the percentage of tdTomato-positive cells (S1A Fig)
Knocking down Sumo2 up-regulated the expression of murine endogenous retrovirus (ERV)-L (MERVL) and other classic 2C-specific genes including double homeobox (Dux), Cml2, zinc finger protein 352 (Zfp352), and Zscan4d (S1B Fig)
Summary
Zygotic genome activation (ZGA) occurs predominantly at the 2-cell (2C) stage of mouse embryo and 4- to 8-cell stages in human embryo [1,2,3], which is essential for the development control passed from maternal to newly synthesized RNA and proteins. Any wrongdoing during ZGA may lead to termination of embryo development or have severe and long-term consequences for the life of an organism. The molecular regulation of ZGA in mammal is poorly understood. A rare subset of cells called 2C-like cells were found in mouse embryonic stem cell (ESC) cultures [4,5].
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