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<p>X-chromosome inactivation (XCI) balances gene expression between sexes in mammals and is essential to female development. XCI initiation strictly relies on the upregulation of long noncoding RNA <i>Xist</i> upon differentiation. Despite the co-occurrence and tight correlation between XCI and differentiation, master coordinators to synchronize XCI and differentiation&#xa0;remain ill-defined. Here, we report that FGF4, an autocrine differentiation-prompting stimulus, is essential for <i>Xist</i> upregulation and XCI initiation&#xa0;in mouse embryonic stem cells (ESCs). Either <i>Fgf4</i> deficiency or FGFR blocking results in failure of <i>Xist</i> upregulation and XCI initiation. Mechanistically, FGF4 initiates XCI in a MEK/ERK-dependent manner, via two parallel but opposing pathways:&#xa0;i)FGF4 phosphorylates and activates YY1, a&#xa0;robust transcription activator of <i>Xist</i>, and ii) FGF4&#xa0;facilitates decline of pluripotency factors&#xa0;<i>Prdm14</i>, <i>Nanog</i> and <i>Rex1</i>, resolving&#xa0;<i>Xist</i> repression. Together, we show how FGF4 comprehensively orchestrates XCI and ESC&#xa0;differentiation, and ensures XCI initiation by coordinating two opposing regulators that directly influence <i>Xist</i> transcription. The FGF-ERK-YY1 axis also constitutes&#xa0; a&#xa0;missing link between ubiquitously expressed <i>Yy1</i> and its functional activation responsible for <i>Xist</i> upregulation and XCI initiation.</p>

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FGF4 initiates X-chromosome inactivation via activating YY1 and prompting loss of pluripotency factors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Lizhu Ma,
  • Wei Fu,
  • Lei An,
  • Qianying Yang,
  • Ruiqi Hai,
  • Guangyin Xi,
  • Yinjuan Wang,
  • Juan Liu,
  • Chao Zhang,
  • Yao Fu,
  • Zhenni Zhang,
  • Xiaodong Wang,
  • Jianhui Tian

摘要

X-chromosome inactivation (XCI) balances gene expression between sexes in mammals and is essential to female development. XCI initiation strictly relies on the upregulation of long noncoding RNA Xist upon differentiation. Despite the co-occurrence and tight correlation between XCI and differentiation, master coordinators to synchronize XCI and differentiation remain ill-defined. Here, we report that FGF4, an autocrine differentiation-prompting stimulus, is essential for Xist upregulation and XCI initiation in mouse embryonic stem cells (ESCs). Either Fgf4 deficiency or FGFR blocking results in failure of Xist upregulation and XCI initiation. Mechanistically, FGF4 initiates XCI in a MEK/ERK-dependent manner, via two parallel but opposing pathways: i)FGF4 phosphorylates and activates YY1, a robust transcription activator of Xist, and ii) FGF4 facilitates decline of pluripotency factors Prdm14, Nanog and Rex1, resolving Xist repression. Together, we show how FGF4 comprehensively orchestrates XCI and ESC differentiation, and ensures XCI initiation by coordinating two opposing regulators that directly influence Xist transcription. The FGF-ERK-YY1 axis also constitutes  a missing link between ubiquitously expressed Yy1 and its functional activation responsible for Xist upregulation and XCI initiation.