Regulation of miRNA-mediated gene silencing by miRNA precursors

Processing of miRNAs from their precursors to the biologically active mature form is regulated during development and cancer. We show that mouse precursor-miR-151 can bind to and compete with mature miR-151-5p and miR-151-3p for binding sites contained within the complementary regions of the E2f6 mRNA 3′UTR. In agreement, E2f6 mRNA levels were regulated by precursor-miR-151. Conversely, the miR-151-mediated repression of ARHGDIA mRNA was only dependent on the mature miR-151 level as only the mature miRNA was able to bind to the 3′UTR. This suggests that processing of miR-151 can have different effects on separate mRNA targets within a cell. A bioinformatics pipeline revealed additional candidate regions where pre-miRNAs can compete with their mature miRNA counterparts. This was experimentally validated for miR-124 and the SNAI2 3′UTR. Hence, miRNA precursors can serve as post-transcriptional regulators of miRNA activity and are not mere biogenesis intermediates.