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<p>2-cell like cells (2CLC) are a transiently cycling population of cells with totipotent-associated features. Although CTCF depletion induces 2CLC conversion in mouse ESC, whether this reprogramming is a consequence of disrupted higher-order chromatin organization or of CTCF-specific functions remained unclear. Here, we show that depletion of the cohesin release factor WAPL in ESC also promotes 2CLC reprogramming, which is increased by CTCF co-depletion. Single-cell RNA-seq/ATAC-seq analyses in CTCF/WAPL-depleted ESC revealed that chromatin accessibility precedes 2C-associated gene expression. Moreover, we identified ARID3A as a transcription factor that regulates the extent of 2CLC conversion following WAPL/CTCF depletion. Although WAPL or CTCF depletion induces distinct transcriptional changes in human ESC, these do not resemble transcriptional programs of early human embryogenesis, suggesting limited evolutionary conservation. Finally, we demonstrate that 2CLC conversion mediated by alterations in chromatin organization depends on the DPPA2/DUX axis and correlates with nucleolar integrity. Together, these findings establish a mechanistic link between higher-order chromatin organization and totipotency-like cell identity in mice.</p>

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Alterations in chromatin organization promote totipotent-like features in a DPPA2/DUX-dependent manner

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月9日

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  • Grace I Carey,
  • Maria Vega-Sendino,
  • Desiree Tillo,
  • Sarah C Hoelscher,
  • Amir Khan,
  • Ian Taukulis,
  • Teresa Olbrich,
  • Bechara Saykali,
  • Andy D Tran,
  • Bhavya Soni,
  • Anna Lee Fong,
  • Melissa Mikolaj,
  • Adam Harned,
  • Kedar Narayan,
  • Michael J Kruhlak,
  • Michael Kelly,
  • Ning Qing Liu,
  • Elzo de Wit,
  • Sergio Ruiz

摘要

2-cell like cells (2CLC) are a transiently cycling population of cells with totipotent-associated features. Although CTCF depletion induces 2CLC conversion in mouse ESC, whether this reprogramming is a consequence of disrupted higher-order chromatin organization or of CTCF-specific functions remained unclear. Here, we show that depletion of the cohesin release factor WAPL in ESC also promotes 2CLC reprogramming, which is increased by CTCF co-depletion. Single-cell RNA-seq/ATAC-seq analyses in CTCF/WAPL-depleted ESC revealed that chromatin accessibility precedes 2C-associated gene expression. Moreover, we identified ARID3A as a transcription factor that regulates the extent of 2CLC conversion following WAPL/CTCF depletion. Although WAPL or CTCF depletion induces distinct transcriptional changes in human ESC, these do not resemble transcriptional programs of early human embryogenesis, suggesting limited evolutionary conservation. Finally, we demonstrate that 2CLC conversion mediated by alterations in chromatin organization depends on the DPPA2/DUX axis and correlates with nucleolar integrity. Together, these findings establish a mechanistic link between higher-order chromatin organization and totipotency-like cell identity in mice.