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<p>Post-translational modifications (PTMs) have been gradually elucidated in congenital malformations such as cleft palate. Among them, O-GlcNAcylation as a dynamic PTM of proteins regulates various critical biological processes including transcription, translation, and cell fate determination. In this study, a substantial decline in O-linked β-D-N-acetylglucosamine (O-GlcNAc) levels was detected within the palatine plates of all-trans retinoic acid (atRA)-induced cleft palate mice. The role of O-GlcNAc transferase (OGT), the sole enzyme responsible for catalyzing O-GlcNAcylation, was investigated in the process of palatal development. In a zebrafish model, the loss of O-GlcNAc resulted in an elevated prevalence of cleft palate and compromised palatal bone formation. Mechanistically, O-GlcNAcylation of myeloid ecotropic viral integration site 2 (MEIS2), which is mediated by OGT, was found to maintain osteogenic homeostasis by modulating its protein stability through inhibition of ubiquitination. Notably, the serine 237 residue (Ser237) was identified as a critical site for MEIS2 O-GlcNAcylation. Together, the present study uncovers the important function of MEIS2 O-GlcNAcylation in palatal bone development and establishes a novel theoretical framework for understanding the regulatory network of palatal development. This finding may provide novel avenues for the future diagnosis and prevention of cleft palate.</p>

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OGT mediates O-GlcNAcylation of MEIS2 and affects palatal osteogenic development

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月6日

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  • Zhongyin Zhang,
  • Zerui Shan,
  • Xinyu Chen,
  • Yu Xia,
  • Li Meng,
  • Yuxin Zhang,
  • Caihong Wu,
  • Lichan Yuan,
  • Junqing Ma

摘要

Post-translational modifications (PTMs) have been gradually elucidated in congenital malformations such as cleft palate. Among them, O-GlcNAcylation as a dynamic PTM of proteins regulates various critical biological processes including transcription, translation, and cell fate determination. In this study, a substantial decline in O-linked β-D-N-acetylglucosamine (O-GlcNAc) levels was detected within the palatine plates of all-trans retinoic acid (atRA)-induced cleft palate mice. The role of O-GlcNAc transferase (OGT), the sole enzyme responsible for catalyzing O-GlcNAcylation, was investigated in the process of palatal development. In a zebrafish model, the loss of O-GlcNAc resulted in an elevated prevalence of cleft palate and compromised palatal bone formation. Mechanistically, O-GlcNAcylation of myeloid ecotropic viral integration site 2 (MEIS2), which is mediated by OGT, was found to maintain osteogenic homeostasis by modulating its protein stability through inhibition of ubiquitination. Notably, the serine 237 residue (Ser237) was identified as a critical site for MEIS2 O-GlcNAcylation. Together, the present study uncovers the important function of MEIS2 O-GlcNAcylation in palatal bone development and establishes a novel theoretical framework for understanding the regulatory network of palatal development. This finding may provide novel avenues for the future diagnosis and prevention of cleft palate.