m6A modification inhibits miRNA intracellular function favouring their extracellular export and the cell-to-cell communication

Epitranscriptomics represents a new layer of gene expression regulation. Specifically, N6-methyladenosine (m6A) regulates RNA maturation, stability, degradation, and translation. Regarding miRNAs, while it has been reported that m6A impact their biogenesis, no evidence is yet provided on their function. Here we show that m6A modification on specific miRNAs weakens their coupling to AGO2, impairs their function on target mRNAs, determines their delivery into extracellular vesicles (EVs) and provides functional information to receiving cells. Mechanistically, the intracellular functional impairment is caused by m6A-mediated inhibition of AGO2/miRNA interaction, the EV-loading is favoured by m6A-mediated recognition by the RBP hnRNPA2B1, the EV-miRNAs function in the receiving cell requires their FTO-mediated demethylation. Consequently, cells express specific miRNAs that do not impact endogenous transcripts but provide regulatory information for cell-to-cell communication. This highlights that a further level of complexity should be considered when relating cellular dynamics to specific miRNAs.