DPPA2/4 and SUMO E3 ligase PIAS4 opposingly regulate zygotic transcriptional program

PLoS Biol. 2019 Jun 21;17(6):e3000324. doi: 10.1371/journal.pbio.3000324. eCollection 2019 Jun.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Embryonic Development / genetics
  • Embryonic Stem Cells / metabolism
  • Female
  • Genome
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / physiology
  • Poly-ADP-Ribose Binding Proteins
  • Protein Inhibitors of Activated STAT / metabolism*
  • Protein Inhibitors of Activated STAT / physiology
  • SUMO-1 Protein / metabolism
  • SUMO-1 Protein / physiology
  • Single-Cell Analysis
  • Sumoylation
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Protein Ligases / physiology
  • Zygote / metabolism

Substances

  • DNA-Binding Proteins
  • DPPA2 protein, human
  • Dppa2 protein, mouse
  • Dppa4 protein, mouse
  • Nuclear Proteins
  • PIAS4 protein, human
  • Poly-ADP-Ribose Binding Proteins
  • Protein Inhibitors of Activated STAT
  • SUMO-1 Protein
  • Transcription Factors
  • Ubiquitin-Protein Ligases

Grants and funding

This study was supported by The National Key Research and Development Program of China (2016YFA0100701, 2018YFA0107601, and 2017YFA0102802) (http://www.most.gov.cn/eng/programmes1/200610/t20061009_36224.htm) and the National Natural Science Foundation of China (31471222, 91640116, 31821091, 31622033, and 91740115) (http://www.nsfc.gov.cn/english/site_1/index.html) to YW and JN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.