Regulation of microRNA-mediated gene silencing by microRNA precursors

miRNAs are a class of about 1,000 noncoding RNAs that in mammals regulate about half of the protein-encoding genes by enhancing their degradation or preventing their translation1,2. After transcription, the long primary miRNA (pri-miRNA) transcripts are processed to 60to 80-nt precursor miRNAs (pre-miRNAs) and are subsequently cleaved to mature ~22-nt-long duplex RNAs3,4. With a few exceptions5,6, the pre-miRNAs have been considered to be mere intermediates of the miRNA biogenesis pathway rather than gene regulators by themselves. The miRNA pathway is controlled by transcriptional and posttranscriptional regulation in a tissueand developmental stage– specific manner7,8. Various steps of miRNA biogenesis are also specifically regulated during differentiation and tumor development, thus resulting in altered ratios of the mature and intermediate miRNA species in these processes9–12 (also reviewed in refs. 13–16). RNA editing17,18 of miRNAs represents an important post-transcriptional mechanism to regulate miRNA expression19,20. The precursor of miR-151, a LINE-2 repetitive element–encoded miRNA, is A-to-I edited, and interestingly this inhibits its further processing by Dicer21. This editing results in an accumulation of edited precursor and reduced levels of mature miR-151 in the mammalian brain. However, the fate of the edited miR-151 precursor is not known, nor is the importance of miR-151 editing in brain well appreciated. Although various mechanisms have been uncovered that can potentially regulate the expression of mature miRNAs, others have been deciphered that regulate the activity of the mature miRNAs, including RNA editing22, target mimicry, and competition with endogenous RNAs and circular RNAs23–28. Here we show that miRNA precursors act as a new class of post-transcriptional regulators of miRNA activity. Paradoxically, these precursors, including the edited miR-151 precursor, can compete with their own mature counterparts to bind to the overlapping miRNA-response elements (MREs) in the 3′ UTRs of target genes to regulate their expression. These specific events may shed new insight into the observed changes in some cancers in which components of the miRNA pathway and specific miRNAs are misregulated.