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

Post-translational modifications (PTMs) in congenital malformations like cleft palate are gradually being elucidated. It has been shown that O-GlcNAcylation as a dynamic PTM of proteins regulates various critical biological processes such as transcription, translation and cell fate determination. In this study, a substantial decline was detected in O-linked β-D-N-acetylglucosamine (O-GlcNAc) levels within the palatine plates of all-trans retinoic acid (atRA)-induced cleft palate mice. The role of O-GlcNAc transferase (OGT), the sole transferase of O-GlcNAc, in the process of palatal development was investigated. In a zebrafish model, the absence 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, regulates palatal osteogenesis homeostasis by inhibiting the stability of MEIS2, a key gene in palatal osteogenesis, via ubiquitination inhibition. Notably, the serine 237 residue (Ser237) of MEIS2 was also identified as a critical site for O-GlcNAcylation. The present study uncovers the important function of MEIS2 O-GlcNAcylation in palatal bone development and thus establishes a novel theoretical framework for the regulatory network of palatal development. This finding may provide novel avenues for the future diagnosis and prevention of cleft palate.