Zscan4 mediates ubiquitination and degradation of the corepressor complex to promote chromatin accessibility in 2C-like cells

Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2407490121. doi: 10.1073/pnas.2407490121. Epub 2024 Dec 20.

Abstract

Zygotic genome activation occurs in two-cell (2C) embryos, and a 2C-like state is also activated in sporadic (~1%) naïve embryonic stem cells in mice. Elevated chromatin accessibility is critical for the 2C-like state to occur, yet the underlying molecular mechanisms remain elusive. Zscan4 exhibits burst expression in 2C embryos and 2C-like cells. Here, we show that Zscan4 mediates chromatin remodeling to promote the chromatin accessibility for achieving the 2C-like state. Through coimmunoprecipitation/mass spectrometry, we identified that Zscan4 interacts with the corepressors Kap1/Trim28, Lsd1, and Hdac1, also with H3K9me3 modifiers Suv39h1/2, to transiently form a repressive chromatin complex. Then, Zscan4 mediates the degradation of these chromatin repressors by recruiting Trim25 as an E3 ligase, enabling the ubiquitination of Lsd1, Hdac1, and Suv39h1/2. Degradation of the chromatin repressors promotes the chromatin accessibility for activation of the 2C-like state. These findings reveal the molecular insights into the roles of Zscan4 in promoting full activation of the 2C-like state.

Keywords: 2C like state; Zscan4; chromatin accessibility; ubiquitination; zygotic genome activation.

MeSH terms

  • Animals
  • Chromatin Assembly and Disassembly
  • Chromatin* / metabolism
  • Histone Deacetylase 1 / genetics
  • Histone Deacetylase 1 / metabolism
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism
  • Humans
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Proteolysis
  • Repressor Proteins* / genetics
  • Repressor Proteins* / metabolism
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Tripartite Motif-Containing Protein 28 / genetics
  • Tripartite Motif-Containing Protein 28 / metabolism
  • Ubiquitination*

Substances

  • Chromatin
  • Repressor Proteins
  • Transcription Factors
  • Histone Deacetylase 1
  • Histone Demethylases
  • Tripartite Motif-Containing Protein 28
  • Methyltransferases