Competition effects regulating the composition of the microRNA pool.

Abstract

MicroRNAS (miRNAs) are short non-coding RNAs that can repress mRNA translation to regulate protein synthesis. During their maturation, multiple types of pre-miRNAs compete for a shared pool of the enzyme Dicer. It is unknown how this competition for a shared resource influences the relative expression of mature miRNAs. We study this process in a computational model of pre-miRNA maturation, fitted to <i>in vitro Drosophila</i> S2 cell data. We find that those pre-miRNAs that efficiently interact with Dicer outcompete other pre-miRNAs, when Dicer is scarce. To test our model predictions, we re-analysed previously published <i>ex vivo</i> mouse striatum data with reduced <i>Dicer1</i> expression. We calculated a proxy measure for pre-miRNA affinity to TRBP (a protein that loads pre-miRNAs to Dicer). This measures well-predicted mature miRNA levels in the data, validating our assumptions. We used this as a basis to test the the model's predictions through further analysis of the data. We found that pre-miRNAs with strong TRBP association are over-represented in competition conditions, consistent with the modelling. Finally using further simulations, we discovered that pre-miRNAs with low maturation rates can affect the mature miRNA pool via competition among pre-miRNAs. Overall, this work presents evidence of pre-miRNA competition regulating the composition of mature miRNAs.