Fig. 6

Representation of the miRNA methylation pathway compared to the canonical pathway of miRNA biogenesis (grey box). The miRNA biogenesis canonical pathway includes the production of the primary miRNA transcript (pri-miRNA) by the RNA polymerase II, and cleavage of the pri-miRNA by the microprocessor complex Drosha–DGCR8 in the nucleus. The resulting precursor hairpin, the pre-miRNA, is exported from the nucleus by Exportin-5. In the cytosol, the RNase Dicer in complex with the double-stranded RNA-binding protein TRBP cleaves the pre-miRNA hairpin to its mature length. The functional strand of the mature miRNA is loaded together with Argonaute and GW182 proteins into the RNA-induced silencing complex (RISC), where it guides RISC to silence target mRNAs and promote translational repression. The miRNA methylation pathway involves the AGO4/DNMT3A-including complex that catalyzes miRNA methylation in the cytosol, leading to the inhibition of its repressive function