Acetylation-triggered degradation of MSX1 impairs palatal development

Area of Science:

• Developmental Biology
• Molecular Biology
• Genetics

Background:

• Cleft palate is a common congenital disorder resulting from disrupted embryonic palatal fusion.
• The role of posttranslational modifications (PTMs) in palatal fusion is not well understood.

Purpose of the Study:

• To investigate the role of lysine acetylation in regulating MSX1 protein stability and its impact on embryonic palatal mesenchymal (EPM) cell survival.
• To explore the potential of targeting MSX1 acetylation for cleft palate prevention and therapy.

Main Methods:

• In vitro and in vivo studies using atRA-induced cleft palate models.
• Analysis of MSX1 protein stability, acetylation, and degradation.
• Transcriptomic profiling to assess the role of acetylation.
• Lentivirus-mediated gene delivery to modulate SIRT1 and MSX1 K139R.

Main Results:

• Lysine acetylation acts as a critical switch for MSX1 proteostasis, governing EPM cell survival.
• SIRT1-catalyzed acetylation regulates MSX1 protein stability, influencing EPM apoptosis and palatal fusion.
• SIRT1 suppression leads to MSX1 hyperacetylation, proteasomal degradation, and EPM apoptosis in cleft palate models.
• Acetylation exclusively affects MSX1 structural stability, not its transcriptional activity.
• Delivery of SIRT1 or MSX1 K139R reduced cleft severity in models.

Conclusions:

• MSX1 acetylation is a pathogenic driver and a druggable target in cleft palate.
• PTM regulation is a central etiological factor in genetic disorders like cleft palate.
• Targeting MSX1 acetylation presents a promising preventive and therapeutic strategy for cleft palate.