Competition effects regulating the composition of the microRNA pool

Abstract

AbstractMicroRNAS (miRNAs) are short non-coding RNAs that can repress mRNA translation to regulate localised protein synthesis. MiRNAs are matured in two steps: first primary-miRNA is processed into pre-miRNA by Drosha in the nucleus, then, following export to the cytosol, pre-miRNA is matured to miRNA by Dicer. Several pre-miRNA attributes affect maturation efficiency, and multiple pre-miRNAs are likely to compete for a limited pool of Dicer. However it is unknown how this competition influences the relative expression of mature miRNAs. Here, we study this in a model of pre-miRNA maturation fitted to experimental data. We find that pre-miRNAs that readily associate with Dicer, and pre-miRNAs with efficient processing by Dicer, are preferentially matured in competitive conditions when Dicer is scarce. To test our model predictions, we re-analysed previously published experimental data with reducedDicer1mRNA expressionin vivo. We calculated a proxy measure for pre-miRNA affinity to TRBP (a protein which loads pre-miRNAs to Dicer). According to our model, proteins with high TRBP affinity should outcompete proteins with low TRBP affinity. Accordingly, we found that pre-miRNAs with stronger TRBP association are more efficiently matured, which validated our proxy measure. We also found that pre-miRNAs with strong TRBP association are over-represented in competition conditions, consistent with our model predictions. Finally, using further simulations, we discovered that pre-miRNAs with low maturation rates can regulate the composition of mature miRNA through competition among pre-miRNAs. Overall, this work presents evidence of pre-miRNA competition regulating the composition of mature miRNAs.