A Modelling Framework for Gene Regulatory Networks Including Transcription and Translation

Abstract

Qualitative models of gene regulatory networks have generally considered transcription factors to regulate directly the expression of other transcription factors, without any intermediate variables. In fact, gene expression always involves transcription, which produces mRNA molecules, followed by translation, which produces protein molecules, which can then act as transcription factors for other genes (in some cases after post-transcriptional modifications). Suppressing these multiple steps implicitly assumes that the qualitative behaviour does not depend on them. Here we explore a class of expanded models that explicitly includes both transcription and translation, keeping track of both mRNA and protein concentrations. We mainly deal with regulation functions that are steep sigmoids or step functions, as is often done in protein-only models. We find that flow cannot be constrained to switching domains, though there can still be asymptotic approach to singular stationary points (fixed points in the vicinity of switching thresholds). This avoids the thorny issue of singular flow, but leads to somewhat more complicated possibilities for flow between threshold crossings. In the infinitely fast limit of either mRNA or protein rates, we find that solutions converge uniformly to solutions of the corresponding protein-only model on arbitrary finite time intervals. This leaves open the possibility that the limit system (with one type of variable infinitely fast) may have different asymptotic behaviour, and indeed, we find an example in which stability of a fixed point in the protein-only model is lost in the expanded model. Our results thus show that including mRNA as a variable may change the behaviour of solutions.