On the role of extrinsic noise in microRNA-mediated bimodal gene expression

Several studies highlighted the relevance of extrinsic noise in shaping cell decision making and differentiation in molecular networks. Bimodal distributions of gene expression levels provide experimental evidence of phenotypic differentiation, where the modes of the distribution often correspond to different physiological states of the system. We theoretically address the presence of bimodal phenotypes in the context of microRNA (miRNA)-mediated regulation. MiRNAs are small noncoding RNA molecules that downregulate the expression of their target mRNAs. The nature of this interaction is titrative and induces a threshold effect: below a given target transcription rate almost no mRNAs are free and available for translation. We investigate the effect of extrinsic noise on the system by introducing a fluctuating miRNA-transcription rate. We find that the presence of extrinsic noise favours the presence of bimodal target distributions which can be observed for a wider range of parameters compared to the case with intrinsic noise only and for lower miRNA-target interaction strength. Our results suggest that combining threshold-inducing interactions with extrinsic noise provides a simple and robust mechanism for obtaining bimodal populations without requiring fine tuning. Furthermore, we characterise the protein distribution’s dependence on protein half-life.Author summary: Phenotypic differentiation often relies on bimodal distributions of gene expression levels, which can normally be achieved by different molecular mechanisms. During the past decade microRNAs, small noncoding RNA molecules, were found to downregulate the expression of preferred mRNA targets by sequestering and successively degrading them, thus influencing the level of gene expression. We theoretically address the question on how microRNA-mediated regulation can induce the appearance of bimodal phenotypes. Our findings show that the presence of extrinsic noise favours bimodal distributions. This suggests a simple mechanism for obtaining bimodal populations where the presence of extrinsic noise relaxes the requirements on parameters fine tuning.