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<p>Stem cell pluripotency relies on a finely tuned interplay between transcription factors and epigenetic regulators. Here, we identify a direct interaction between NANOG, a master pluripotency transcription factor, and WDR5, a core chromatin regulator essential for maintaining stem cell identity. Mechanistically, WDR5 remodels irregular NANOG aggregates into dynamic, liquid-liquid phase-separated condensates at pluripotency-associated promoters to activate target genes. Structural analyses show that the NANOG homeodomain engages WDR5 through an extended interface distinct from previously characterized short linear motifs. The NANOG R153A mutation disrupts this interaction, leading to impaired condensate formation, reduced chromatin co-occupancy, and diminished levels of active histone marks, ultimately compromising embryonic stem cell pluripotency. Pharmacological inhibition of the WDR5-NANOG interaction suppresses leukemia stem cell expansion in vivo, highlighting its therapeutic potential. Collectively, this study reveals that WDR5-dependent regulation of NANOG condensate dynamics links phase-separated assemblies to transcriptional control of stem cell identity in physiological and pathological contexts.</p>

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WDR5 remodels NANOG condensates to drive transcriptional programs and sustain stem cell identity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Duo Wang,
  • Xianle Shi,
  • Jiaying Xie,
  • Lijie Zhao,
  • Bin Wu,
  • Qiman Dong,
  • Yaoguang Huang,
  • Jinlong Suo,
  • Xinyu Wang,
  • Beixuan He,
  • Shukun Yan,
  • Hongjuan Xue,
  • Yuheng Shi,
  • Yingbin Liu,
  • Jianlong Wang,
  • Yong Chen,
  • Yanjing Li

摘要

Stem cell pluripotency relies on a finely tuned interplay between transcription factors and epigenetic regulators. Here, we identify a direct interaction between NANOG, a master pluripotency transcription factor, and WDR5, a core chromatin regulator essential for maintaining stem cell identity. Mechanistically, WDR5 remodels irregular NANOG aggregates into dynamic, liquid-liquid phase-separated condensates at pluripotency-associated promoters to activate target genes. Structural analyses show that the NANOG homeodomain engages WDR5 through an extended interface distinct from previously characterized short linear motifs. The NANOG R153A mutation disrupts this interaction, leading to impaired condensate formation, reduced chromatin co-occupancy, and diminished levels of active histone marks, ultimately compromising embryonic stem cell pluripotency. Pharmacological inhibition of the WDR5-NANOG interaction suppresses leukemia stem cell expansion in vivo, highlighting its therapeutic potential. Collectively, this study reveals that WDR5-dependent regulation of NANOG condensate dynamics links phase-separated assemblies to transcriptional control of stem cell identity in physiological and pathological contexts.