Folate deficiency disturbs hsa‐let‐7 g level through methylation regulation in neural tube defects

Folic acid deficiency during pregnancy is believed to be a high‐risk factor for neural tube defects ( NTD s). Disturbed epigenetic modifications, including mi RNA regulation, have been linked to the pathogenesis of NTD s in those with folate deficiency. However, the mechanism by which folic acid‐regulated mi RNA influences this pathogenesis remains unclear. It is believed that DNA methylation is associated with dysregulated mi RNA expression. To clarify this issue, here we measured the methylation changes of 22 mi RNA s in 57 human NTD cases to explore whether such changes are involved in mi RNA regulation in NTD cases through folate metabolism. In total, eight of the 22 mi RNA s tested reduced their methylation modifications in NTD cases, which provide direct evidence of the roles of interactions between DNA methylation and mi RNA level in these defects. Among the findings, there was a significant association between folic acid concentration and hsa‐let‐7 g methylation level in NTD cases. Hypomethylation of hsa‐let‐7 g increased its own expression level in both NTD cases and cell models, which indicated that hsa‐let‐7 g methylation directly regulates its own expression. Overexpression of hsa‐let‐7 g, along with its target genes, disturbed the migration and proliferation of SK ‐N‐ SH cells, implying that hsa‐let‐7 g plays important roles in the prevention of NTD s by folic acid. In summary, our data suggest a relationship between aberrant methylation of hsa‐let‐7 g and disturbed folate metabolism in NTD s, implying that improvements in nutrition during early pregnancy may prevent such defects, possibly via the donation of methyl groups for mi RNA s.