2. Academic Validation
  3. Gcm1 Orchestrates Lef1 Expression in Folate Deficiency-Induced Neural Tube Defects

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

  • Mol Neurobiol. 2025 Nov 11;63(1):29. doi: 10.1007/s12035-025-05346-x.
Zhihua Cao # 1 2,  Lu Li # 1,  Xiaolong Gu # 1,  Baolian Li 3,  Qi Xie 1,  Xuefen Wu 1,  Xinhuan Zhang 4,  Guohua Zhang 4,  Ke Wu 5,  Wenbing Ren 1,  Zhizhen Liu 1,  Aili Fang 6,  Shenghui Lu 7,  Qiu Xie 8 9,  Jianting Li 10
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, College of Basic Medicine, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan, 030001, PR China.
  • 2 First Clinical College, Shanxi Medical University, Taiyuan, 030001, PR China.
  • 3 Department of Gynecology, Lvliang People's Hospital, Lvliang, 033000, PR China.
  • 4 Department of Obstetrics, First Clinical College of Shanxi Medical University, Taiyuan, 030001, PR China.
  • 5 Academy of Medical Sciences, Shanxi Medical University, Taiyuan, 030001, PR China.
  • 6 Department of Anesthesiology, Bethune Hospital of Shanxi Medical University, Taiyuan, 030001, PR China.
  • 7 Department of Obstetrics, First Clinical College of Shanxi Medical University, Taiyuan, 030001, PR China. [email protected].
  • 8 State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100850, China. [email protected].
  • 9 NHC Key Laboratory of Birth Defects Prevention, Henan, China. [email protected].
  • 10 Department of Biochemistry and Molecular Biology, College of Basic Medicine, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention, Shanxi Medical University, Taiyuan, 030001, PR China. [email protected].
  • # Contributed equally.
PMID: 41217685 DOI: 10.1007/s12035-025-05346-x
Abstract

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.

Keywords

Acetylation; CREB-binding protein; Glial cell missing 1; Lymphoid enhancer binding factor 1; Neural tube defects.

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