The contribution of microRNA-mediated regulation to short- and long-term gene expression predictability

MicroRNAs are a class of short, noncoding RNAs which are essential for the coordination and timing of cell differentiation and embryonic development. However, despite their guiding role in development, microRNAs are dysregulated in many pathologies, including nearly all cases of cancer. While both development and oncogenesis can be thought of as extremes of phenotypic plasticity, they characteristically manifest on much different time scales: one taking place over a matter of weeks, the other typically requiring decades. Because microRNAs are believed to support this plasticity, a critically important question is how microRNAs affect phenotypic stability on different time scales, and what dynamical characteristics shift the balance between these two roles. To address this question, we extend a well-established mathematical model of transcriptional gene regulation to include translational regulation by microRNAs, and examine their effects on both short- and long-term gene expression predictability. Our findings show that microRNAs greatly improve short-term predictability for earlier, developmental phenotypes while causing a small decrease in long-term predictability, and that these effects are difficult to separate. In addition to providing a theoretical explanation for this seemingly duplicitous behavior, we describe some of the properties which determine the cost-benefit balance between short-term stabilization and long-term destabilization.