Dynamical modeling of microRNA action on the protein translation process

Abstract

BackgroundProtein translation is a multistep process which can be represented as a cascade of biochemical reactions (initiation, ribosome assembly, elongation, etc.), the rate of which can be regulated by small non-coding microRNAs through multiple mechanisms. It remains unclear what mechanisms of microRNA action are the most dominant: moreover, many experimental reports deliver controversial messages on what is the concrete mechanism actually observed in the experiment. Nissan and Parker have recently demonstrated that it might be impossible to distinguish alternative biological hypotheses using the steady state data on the rate of protein synthesis. For their analysis they used two simple kinetic models of protein translation.ResultsIn contrary to the study by Nissan and Parker, we show that dynamical data allow discriminating some of the mechanisms of microRNA action. We demonstrate this using the same models as developed by Nissan and Parker for the sake of comparison but the methods developed (asymptotology of biochemical networks) can be used for other models. We formulate a hypothesis that the effect of microRNA action is measurable and observable only if it affects the dominant system (generalization of the limiting step notion for complex networks) of the protein translation machinery. The dominant system can vary in different experimental conditions that can partially explain the existing controversy of some of the experimental data.ConclusionsOur analysis of the transient protein translation dynamics shows that it gives enough information to verify or reject a hypothesis about a particular molecular mechanism of microRNA action on protein translation. For multiscale systems only that action of microRNA is distinguishable which affects the parameters of dominant system (critical parameters), or changes the dominant system itself. Dominant systems generalize and further develop the old and very popular idea of limiting step. Algorithms for identifying dominant systems in multiscale kinetic models are straightforward but not trivial and depend only on the ordering of the model parameters but not on their concrete values. Asymptotic approach to kinetic models allows putting in order diverse experimental observations in complex situations when many alternative hypotheses co-exist.

Integrated microRNA and mRNA expression profiling in a rat colon carcinogenesis model: effect of a chemo-protective diet

“…The large-scale prediction of targets across the whole genome allowed us to achieve a higher degree of specificity of prediction and to infer the regulatory activities of microRNAs in the colon. To date, a number of studies have utilized statistical/systems biology methodologies to identify microRNAs that may target genes in response to a pathophysiological state (31,44,88). However, there is a paucity of integrative microRNA and mRNA expression studies that focus on early-stage colon cancer development and chemoprevention.…”

Kinetic signatures of microRNA modes of action

“…The mathematical approach we have developed here for analysis of the complete model of microRNA action is based on the general theory of dynamical limitation and uses the notion of a dominant dynamical system, itself a generalization of the rate-limiting step concept to complex networks Gorban et al 2010;Zinovyev et al 2010). The idea that microRNA action will not have a visible impact on inhibition of translational initiation unless this is the rate-limiting step in protein translation has already been mentioned in the work by Nissan and Parker (2008).…”

“…Sensitive parameters of the dominant system indicate putative targets that will change the behavior of the large network. Some applications of this approach to systems biology were presented in Radulescu et al (2008) and Zinovyev et al (2010).…”

“…The relaxation time is the time between microRNA application to the system and stabilization of the system, meaning reaching new steady-state levels of mRNA and protein. This parameter can be determined from the kinetic signature plots (for a more detailed explanation, see Zinovyev et al 2010) and the experimental data, and then compared.…”

“…Repression of protein translation by miRNA has already been the subject of mathematical modeling (Nissan and Parker 2008;Zinovyev et al 2010). However, a computational tool for discriminating among all proposed mechanisms of miRNA action remains to be developed.…”