ANALYSIS OF EPIGENETIC FACTORS IN MOUSE EMBRYONIC NEURAL STEM CELLS EXPOSED TO HIGH GLUCOSE

Abstract

Background: Maternal diabetes alters gene expression leading to neural tube defects (NTD) in the developing brain. The mechanistic pathways that deregulate the gene expression remain unknown. It is hypothesized that exposure of neural stem cells (NSCs) to high glucose/hyperglycemia results in activation of epigenetic mechanisms which alter gene expression and cell fate during brain development. Results: In order to examine hyperglycemia induced epigenetic changes in NSCs, chromatin reorganization, global histone status at lysine 9 residue of histone H3 (acetylation and trimethylation) and global DNA methylation were examined and found to be altered by hyperglycemia. Exposure to hyperglycemia altered the expression of specific microRNAs (mmu-miR-200a, mmu-miR-200b, mmu-miR-466a-3p and mmu-miR-466 d-3p) that regulate NSC fate. Further, global microRNA profiling and pathway analysis revealed differential expression of microRNAs that regulate genes (pathways) critical for neural tube development. Conclusion/interpretation: This study revealed that hyperglycemia alters the epigenetic mechanisms in NSCs, resulting in altered expression of some development control genes which may form the basis for the NTD. Overall, the results provide novel insights into the mechanism of maternal diabetes-induced NTD.