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<p>Maintenance of pluripotency in embryonic stem cells (ESCs) requires coordinated integration of transcriptional, metabolic, and epigenetic programs. Here, we identify a post-transcriptional regulatory axis linking the RNA-binding protein Musashi-1 (MSI1) to iron dependent DNA demethylation via the ferritin like gene <i>Fthl17c</i>. Genetic ablation of MSI1 and its short isoform MSI1-C in mESCs induced spontaneous differentiation and was accompanied by downregulation of <i>Fthl17</i> family genes. Among these, <i>Fthl17c</i> was directly bound and stabilized by MSI1, and its depletion reduced intracellular ferrous iron (Fe<sup>2</sup>⁺), impaired ten eleven translocation (TET) enzyme activity, and increased global 5-methylcytosine (5mC) levels. Restoration of <i>Fthl17c</i> expression rescued TET activity, reduced DNA methylation, and reinstated pluripotency associated gene expression, whereas extracellular Fe<sup>2</sup>⁺ supplementation alone was insufficient. In contrast, vitamin C, which preserves redox active Fe<sup>2</sup>⁺, effectively restored DNA demethylation, highlighting the requirement for bioavailable iron in TET mediated epigenetic regulation. Biochemical and imaging analyses further revealed that FTHL17C interacts with TET1 in the nucleus, supporting a role in facilitating iron dependent catalysis. Together, these findings define an MSI1-FTHL17C-Fe<sup>2</sup>⁺-TET axis that integrates post transcriptional control of iron homeostasis with epigenetic remodeling to preserve the pluripotent and plastic state of embryonic stem cells.</p>

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MSI1-FTHL17C-iron circuit couples metabolic and epigenetic control of pluripotency in mouse embryonic stem cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月6日

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  • Qianyan Li,
  • Yi Li,
  • Jiazhen Han,
  • Liming Cheng,
  • Gufa Lin,
  • Youwei Chen

摘要

Maintenance of pluripotency in embryonic stem cells (ESCs) requires coordinated integration of transcriptional, metabolic, and epigenetic programs. Here, we identify a post-transcriptional regulatory axis linking the RNA-binding protein Musashi-1 (MSI1) to iron dependent DNA demethylation via the ferritin like gene Fthl17c. Genetic ablation of MSI1 and its short isoform MSI1-C in mESCs induced spontaneous differentiation and was accompanied by downregulation of Fthl17 family genes. Among these, Fthl17c was directly bound and stabilized by MSI1, and its depletion reduced intracellular ferrous iron (Fe2⁺), impaired ten eleven translocation (TET) enzyme activity, and increased global 5-methylcytosine (5mC) levels. Restoration of Fthl17c expression rescued TET activity, reduced DNA methylation, and reinstated pluripotency associated gene expression, whereas extracellular Fe2⁺ supplementation alone was insufficient. In contrast, vitamin C, which preserves redox active Fe2⁺, effectively restored DNA demethylation, highlighting the requirement for bioavailable iron in TET mediated epigenetic regulation. Biochemical and imaging analyses further revealed that FTHL17C interacts with TET1 in the nucleus, supporting a role in facilitating iron dependent catalysis. Together, these findings define an MSI1-FTHL17C-Fe2⁺-TET axis that integrates post transcriptional control of iron homeostasis with epigenetic remodeling to preserve the pluripotent and plastic state of embryonic stem cells.