Impact of competition between precursor and mature microRNAs on stochastic gene expression

MicroRNAs (miRNAs) are key post-transcriptional regulators, processed from precursor miRNAs (pre-miRNAs) into mature miRNAs through nuclear and cytoplasmic proteins. Recent evidence shows that pre-miRNAs and mature miRNAs can compete for the same target mRNAs, yet the impact of this miRNA maturation-driven competition on gene expression noise remains unknown. We address this in widespread feedback motifs where both pre-miRNAs and mature miRNAs degrade a protein's transcripts, and the protein itself either activates or represses miRNA transcription. Using a mathematical model, we show that miRNA maturation tunes the behavior of positive or negative feedback loops, which function as bistable switches or oscillators at the mean-field level, respectively. The relative degradation of mature versus pre-miRNAs and the mRNA-miRNA co-degradation rates can jointly modulate the parameter regions of bistability or oscillations. Moreover, for positive feedback, stochastic simulations reveal that bimodal mRNA distributions emerge near the saddle-node bifurcation boundaries, but not always within the bistable regions. Bimodal mRNA distributions also appear for negative feedback, but outside the region of limit cycles. Importantly, in both feedback types, such noise-induced bimodality emerges in regions where mean-field analysis predicts no bistability or limit cycles. These results demonstrate that noise-induced phenotypic variability cannot necessarily be linked to underlying deterministic bifurcations and elucidate how miRNA maturation shapes stochastic gene expression in regulatory motifs relevant to development and disease.