Dynamics of actively regulated gene networks

A popular way of modelling gene regulatory networks is to design the models as if the genes were acting directly on each other. Genes are activated or inhibited by transcription factors which are direct gene products. The action of a transcription factor on a gene is modelled as a binary on-off dose-response function or a sigmoid around a certain threshold concentration. A transcription factor may act on several genes with equal or different thresholds. The combined effect of several transcription factors on a gene is generally assumed to obey Boolean-like composition rules. A mathematical challenge related to such network models is to analyse the behaviour in the narrow domains in phase space where at least one variable is close to one of its thresholds, called switching domains. In the present paper we analyse the motion in switching domains for models with steep sigmoidal response functions under the assumption that each transcription factor only regulates one gene at each of its thresholds. This biologically reasonable assumption allows us to establish rules that determine the passage through any switching domain and the sequence of domains through which the system passes. The rules can be effectively implemented in a sound automated analyser for such networks. The assumption simplifies certain mathematical and computational issues, but unfortunately may be at variance with one of the necessary conditions for the singular perturbation theory which our derivations are based on. We give sufficient conditions ensuring that, despite this, the difficulties raised by our assumption can be evaded and singular perturbation approximation safely applied. (C) 2010 Elsevier B.V. All rights reserved.