Transcriptome-wide regulation of folate on neural mRNA m6A methylome via carbon metabolism in Drosophila and mammals

Increasing evidence shows that folate can regulate neural gene function through DNA modification, while regulatory roles of folate in neural RNA modification remain largely unknown. Here we show that folate treatment significantly increased Drosophila mRNA m⁶A levels. RNA methylation analysis indicates that carbon metabolism pathways and neural pathways are the mainly affected pathways by folate. Folate can increase mRNA m⁶A modification through carbon metabolic pathway in human cells, especially in neural cells. We also show that folate treatment can significantly increase the expression of m⁶A-related proteins (METTL3, METTL14) and neural mRNA m⁶A methylation levels in mice brain. Moreover, we find that folate-producing Lactobacillus plantarum can increase host mRNA m⁶A modification after colonization. In conclusion, we demonstrate that folate participates in mRNA m⁶A modification through carbon metabolic pathway in both Drosophila and mammals, and our results suggest that folate has a significant effect on neural-related genes and pathways.