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

• N6-methyladenosine (m6A) modifications of RNA exhibit a robust circadian rhythm.
• Deficiency of CRY decreases the levels of m6A modifications in RNA.
• CRY1/2 knockout mice lose the circadian rhythm of m6A modifications in RNA.
• Circadian m6A rhythms correlate with RNA metabolism and transcription/translation.

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.

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