AMBRA1 -mediated autophagy and apoptosis associated with an epithelial-mesenchymal transition in the development of cleft palate induced by all-trans retinoic acid

Background: Autophagy and apoptosis are involved in embryogenesis. However, little is known about the regulatory mechanism of AMBRA1 -mediated autophagy and apoptosis associated with epithelial-mesenchymal transition (EMT) in the development of cleft palate (CP). This study is aimed to elucidate a novel regulatory mechanism by which AMBRA1 regulates autophagy and apoptosis associated with EMT during palatal fusion. Methods: We performed lncRNA and mRNA co-expression profile analysis on embryonic gestation day 14.5 (E14.5) mouse embryos from control (n=3) and all-trans retinoic acid-treated (to induce cleft palate, n=3) C57BL/6J mice. Functional prediction for transcription factor (TF)-target gene relationship, which was obtained using Gene Ontology/Kyoto Encyclopedia of Genes and Genomes analyses (GO/KEGG) pathway analysis, identified the regulatory “lncRNA-TF-target gene” using the trans model. Results: The trans analysis revealed that some TFs (e.g., LEF1, SMAD4 , and FOXD3 ) regulate lncRNA and gene expression. Finally, we identified a NONMMUT034790.2–LEF1–AMBRA1 trans-regulatory network associated with CP. Our results indicate that AMBRA1 might be a novel epigenetic biomarker in palatogenesis. Conclusions: AMBRA1 -mediated autophagy and apoptosis associated with EMT by a NONMMUT034790.2–LEF1–AMBRA1 trans-regulatory network might be an important mechanism underlying dysfunctional palatal fusion.