mRNA-miRNA Reciprocal Regulation Enabled Bistable Switch Directs Cell Fate Decision

TL;DR

This study uses mathematical modeling to reveal how mRNA-miRNA reciprocal regulation can generate bistability, influencing cell fate decisions, even without feedback loops, highlighting a fundamental regulatory mechanism.

Contribution

The paper demonstrates that simple mRNA-miRNA reciprocal regulation can induce bistability, expanding understanding of cell fate regulation mechanisms beyond feedback loops.

Findings

Reciprocal regulation can produce ultrasensitivity and bistability with positive feedback.

Bistability region is expanded by stronger competing mRNA (ceRNA).

Multiple miRNA binding sites can induce bistability without feedback loops.

Abstract

miRNAs serve as crucial post-transcriptional regulators in various essential cell fate decision. However, the contribution of the mRNA-miRNA mutual regulation to bistability is not fully understood. Here, we built a set of mathematical models of mRNA-miRNA interactions and systematically analyzed the sensitivity of response curves under various conditions. First, we found that mRNA-miRNA reciprocal regulation could manifest ultrasensitivity to subserve the generation of bistability when equipped with a positive feedback loop. Second, the region of bistability is expanded by a stronger competing mRNA (ceRNA). Interesting, bistability can be emerged without feedback loop if multiple miRNA binding sites exist on a target mRNA. Thus, we demonstrated the importance of simple mRNA-miRNA reciprocal regulation in cell fate decision.