Investigating Gene Expression Noise Reduction by MicroRNAs and MiRISC Reinforcement by Self-Feedback Regulation of mRNA Degradation

MicroRNA (miRNA) induced silencing complex (miRISC) is the targeting apparatus and arguably rate-limiting step of the miRNA-mediated regulatory subsystem – the major noise reducing though metabolically wasteful mechanism. Recently, we reported that miRISC channels miRNA-mediated regulatory activity back onto their own mRNAs to form negative self-feedback loops, a noise-reduction technique in engineering and synthetic/systems biology. Here, we describe mathematical modeling that predicts mRNA expression noise to correlate negatively with degradation rate (K _deg ) and noise reduction by self-feedback control of K _deg . We also calculated K _deg and expression noise of mRNAs detected in a cutting-edge total-RNA single-cell RNA-seq (scRNA-seq) dataset. As predicted, miRNA-targeted mRNAs exhibited higher K _deg values in conjunction with lower inter-cell expression noise. Moreover, as predicted by our self-feedback loop model, miRISC mRNAs (AGO1/2/3 and TNRC6A/B/C) exhibited further reduced expression noise. In short, mathematical-modeling and total-RNA scRNA-seq data-analysis shed insight into operational trade-off between noise reduction and metabolic/energetic expenditure in producing miRNA-targeted mRNAs destined for enhanced degradation and translational inhibition, as well as negative self-feedback loop reinforcement of miRISC – the core of miRNA-mediated noise-reduction subsystem. To our knowledge, this is the first report of concurrent mRNA degradation and expression noise analyses and of noise reduction by self-feedback control of mRNA degradation.