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<p> Neural tube defects (NTDs) are severe congenital anomalies with limited therapeutic options. Increased expression of the transcription factor glial cell missing 1 (Gcm1) has been linked to NTDs, yet the mechanisms underlying this association remain elusive. Herein, folate deficiency upregulated Gcm1 expression through H4 acetylation (H4ac) enrichment in the promoter. ChIP–qPCR and Co-IP experiments revealed that folate deficiency enhanced H4 acetylation at the Gcm1 promoter via CREB-binding protein (CBP), subsequently resulting in increased Gcm1 transcription. Furthermore, Gcm1-ChIP-seq revealed lymphoid enhancer binding factor 1 (Lef1) as a potential downstream target of Gcm1 in mESCs without folate supplementation and the likely activator of the Wnt/β-catenin pathway for aberrant neurodevelopment. Immunohistochemistry and immunofluorescence analyses revealed significantly higher Gcm1 and Lef1 expression in a low-folate NTD mouse model than in controls. Finally, NanoString analysis of human low-folate NTD samples confirmed a positive correlation between upregulated Gcm1 expression and Lef1 expression. Collectively, these findings indicate that the CBP-dependent Gcm1 regulation of Lef1 expression is crucial in folate-deficient NTDs, revealing the potential mechanism by which NTDs are induced by low folate concentrations and providing a promising target for therapeutic intervention.</p>

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Gcm1 Orchestrates Lef1 Expression in Folate Deficiency-Induced Neural Tube Defects

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月11日

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  • Zhihua Cao,
  • Lu Li,
  • Xiaolong Gu,
  • Baolian Li,
  • Qi Xie,
  • Xuefen Wu,
  • Xinhuan Zhang,
  • Guohua Zhang,
  • Ke Wu,
  • Wenbing Ren,
  • Zhizhen Liu,
  • Aili Fang,
  • Shenghui Lu,
  • Qiu Xie,
  • Jianting Li

摘要

Neural tube defects (NTDs) are severe congenital anomalies with limited therapeutic options. Increased expression of the transcription factor glial cell missing 1 (Gcm1) has been linked to NTDs, yet the mechanisms underlying this association remain elusive. Herein, folate deficiency upregulated Gcm1 expression through H4 acetylation (H4ac) enrichment in the promoter. ChIP–qPCR and Co-IP experiments revealed that folate deficiency enhanced H4 acetylation at the Gcm1 promoter via CREB-binding protein (CBP), subsequently resulting in increased Gcm1 transcription. Furthermore, Gcm1-ChIP-seq revealed lymphoid enhancer binding factor 1 (Lef1) as a potential downstream target of Gcm1 in mESCs without folate supplementation and the likely activator of the Wnt/β-catenin pathway for aberrant neurodevelopment. Immunohistochemistry and immunofluorescence analyses revealed significantly higher Gcm1 and Lef1 expression in a low-folate NTD mouse model than in controls. Finally, NanoString analysis of human low-folate NTD samples confirmed a positive correlation between upregulated Gcm1 expression and Lef1 expression. Collectively, these findings indicate that the CBP-dependent Gcm1 regulation of Lef1 expression is crucial in folate-deficient NTDs, revealing the potential mechanism by which NTDs are induced by low folate concentrations and providing a promising target for therapeutic intervention.