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

The microRNA (miRNA) induced silencing complex (miRISC) is the targeting apparatus and arguably the rate-limiting step of the miRNA-mediated regulatory subsystem - a major noise reducing, though metabolically costly, mechanism. Recently, we reported that miRISC channels miRNA-mediated regulatory activity back onto its own mRNAs to form negative self-feedback loops, a noise-reduction technique in engineering and synthetic/systems biology. In this paper, our mathematical modeling predicts that mRNA expression noise exhibits a negative correlation with the degradation rate ( $K_{deg}$ ) and is attenuated by self-feedback control of degradation. We also calculated $K_{deg}$ and expression noise of mRNAs detected in a total-RNA single-cell RNA-seq (scRNA-seq) dataset. As predicted, miRNA-targeted mRNAs exhibited higher $K_{deg}$ values accompanied by reduced inter-cell expression noise, confirming the operational trade-off between noise suppression and the increased metabolic/energetic costs associated with producing these mRNAs subjected to accelerated degradation and translational inhibition. Moreover, consistent with the $K_{deg}$ self-feedback control model, miRISC mRNAs (AGO1/2/3 and TNRC6A/B/C) exhibited further reduced expression noise. In summary, mathematical-modeling and total-RNA scRNA-seq data-analyses provide evidence that negative self-feedback regulation of mRNA degradation reinforces miRISC, the core machinery of the miRNA-mediated noise-reduction subsystem. To our knowledge, this is the first study to concurrently analyze mRNA degradation dynamics and expression noise, and to demonstrate noise reduction by self-feedback regulation of mRNA degradation.