Reciprocal regulation between mRNA and microRNA enables a bistable switch that directs cell fate decisions

Micro RNAs (miRNAs) serve as crucial post-transcriptional regulators in a variety of essential cell fate decisions. However, the contribution of mRNA-miRNA mutual regulation to bistability is not fully understood. In the present study, we built a set of mathematical models of mRNA-miRNA interactions and systematically analyzed the sensitivity of the response curves under various conditions. Our findings indicate that mRNA-miRNA reciprocal regulation could manifest ultrasensitivity to subserve the generation of bistability when equipped with a positive feedback loop. We also find that the region of bistability is expanded by a stronger competing endogenous mRNA. Interestingly, bistability can be generated without a feedback loop if multiple miRNA binding sites exist on a target mRNA. Thus, we demonstrate the importance of simple mRNA-miRNA reciprocal regulation in cell fate decisions.