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<p>After fertilization, maternally deposited mRNAs are cleared, and de novo transcription is initiated through zygotic genome activation (ZGA), a core event of the maternal-to-zygotic transition in mice. 2-cell-like cells (2CLCs), a rare MERVL-positive subpopulation of mouse embryonic stem cells, partially recapitulate transcriptional features of 2-cell embryos. Although canonical MERVL-high 2CLCs depend on DUX, <i>Dux</i> knockout embryos can develop to term, suggesting that 2CLC models do not fully capture DUX-independent pathways associated with preimplantation transcriptional programs. Here, we show that disruption of C-terminal binding protein 1/2 (Ctbp1/2) activates both DUX-dependent minor ZGA-associated genes and DUX-independent major ZGA- and post-ZGA-associated programs. <i>Pramel7</i> is derepressed independently of DUX and contributes to subsets of both programs. PRAMEL7 overexpression partially rescues transcriptional defects caused by <i>Dux</i> deletion and is associated with UHRF1 downregulation and DNA demethylation-linked activation of post-ZGA-associated genes. These findings identify CtBP1/2 as repressors of multiple early embryonic transcriptional programs in mouse embryonic stem cells.</p>

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CtBP1/2 restrict DUX-dependent and independent 2C-like programs in mouse embryonic stem cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Kazuma Yoshioka,
  • Maki Ichisakino,
  • Kota Sugiyama,
  • Nao Hayakawa,
  • Selma Alamanda Abadi,
  • Heekyoung Yoon,
  • Miyu Marutani,
  • Ryo Masuda,
  • Kyo Takahashi,
  • Yoshiyuki Seki

摘要

After fertilization, maternally deposited mRNAs are cleared, and de novo transcription is initiated through zygotic genome activation (ZGA), a core event of the maternal-to-zygotic transition in mice. 2-cell-like cells (2CLCs), a rare MERVL-positive subpopulation of mouse embryonic stem cells, partially recapitulate transcriptional features of 2-cell embryos. Although canonical MERVL-high 2CLCs depend on DUX, Dux knockout embryos can develop to term, suggesting that 2CLC models do not fully capture DUX-independent pathways associated with preimplantation transcriptional programs. Here, we show that disruption of C-terminal binding protein 1/2 (Ctbp1/2) activates both DUX-dependent minor ZGA-associated genes and DUX-independent major ZGA- and post-ZGA-associated programs. Pramel7 is derepressed independently of DUX and contributes to subsets of both programs. PRAMEL7 overexpression partially rescues transcriptional defects caused by Dux deletion and is associated with UHRF1 downregulation and DNA demethylation-linked activation of post-ZGA-associated genes. These findings identify CtBP1/2 as repressors of multiple early embryonic transcriptional programs in mouse embryonic stem cells.