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.