Mathematical modeling of microRNA-mediated mechanisms of translation repression

TL;DR

This paper develops mathematical models to analyze and interpret the various mechanisms of microRNA-mediated translation repression, aiming to resolve ongoing debates about the dominant mechanisms in different cellular contexts.

Contribution

It introduces a comprehensive mathematical modeling framework that integrates all known miRNA mechanisms to interpret experimental data and identify dominant repression pathways.

Findings

Different miRNA mechanisms can coexist and vary depending on experimental conditions.

The models can generate kinetic signatures to identify the dominant repression mechanism.

The approach explains existing controversies by linking limiting steps to specific mechanisms.

Abstract

MicroRNAs can affect the protein translation using nine mechanistically different mechanisms, including repression of initiation and degradation of the transcript. There is a hot debate in the current literature about which mechanism and in which situations has a dominant role in living cells. The worst, same experimental systems dealing with the same pairs of mRNA and miRNA can provide ambiguous evidences about which is the actual mechanism of translation repression observed in the experiment. We start with reviewing the current knowledge of various mechanisms of miRNA action and suggest that mathematical modeling can help resolving some of the controversial interpretations. We describe three simple mathematical models of miRNA translation that can be used as tools in interpreting the experimental data on the dynamics of protein synthesis. The most complex model developed by us includes all known mechanisms of miRNA action. It allowed us to study possible dynamical patterns corresponding to different miRNA-mediated mechanisms of translation repression and to suggest concrete recipes on determining the dominant mechanism of miRNA action in the form of kinetic signatures. Using computational experiments and systematizing existing evidences from the literature, we justify a hypothesis about co-existence of distinct miRNA-mediated mechanisms of translation repression. The actually observed mechanism will be that acting on or changing the limiting "place" of the translation process. The limiting place can vary from one experimental setting to another. This model explains the majority of existing controversies reported.