Circadian rhythm of RNA N6-methyladenosine and the role of cryptochrome

Methylation of RNA N⁶-methyladenosine has fundamental cellular functions, including translation regulation, RNA export, and stem cells renewal. However, the regulation of RNA N⁶-methyladenosine methylation is poorly understood. Here, we observed a robust circadian rhythm in N⁶-methyladenosine modifications of RNA. Deficiency of core mammalian clock genes, cryptochromes, decreased the levels of N⁶-methyladenosine in RNA. Cryptochrome1/2 knockout mice had significantly lower N⁶-methyladenosine methylation of RNA and lost the circadian rhythm of N⁶-methyladenosine levels in RNA. Global analysis of the circadian methylomes of N⁶-methyladenosine in RNA revealed that gene transcription, translation regulation, and RNA metabolism were highly correlated with N⁶-methyladenosine oscillation. Our findings extended a fundamental link between the circadian rhythm and N⁶-methyladenosine modification of RNA and suggested that this link is critical in controlling post-transcriptional gene expression and RNA metabolism.