title: Diffusion driven oscillations in gene regulatory networks.
abstract: Gene regulatory networks (GRNs) play an important role in maintaining cellular function by correctly timing key processes such as cell division and apoptosis. GRNs are known to contain similar structural components, which describe how genes and proteins within a network interact - typically by feedback. In many GRNs, proteins bind to gene-sites in the nucleus thereby altering the transcription rate. If the binding reduces the transcription rate there is a negative feedback leading to oscillatory behaviour in mRNA and protein levels, both spatially (e.g. by observing fluorescently labelled molecules in single cells) and temporally (e.g. by observing protein/mRNA levels over time). Mathematical modelling of GRNs has focussed on such oscillatory behaviour. Recent computational modelling has demonstrated that spatial movement of the molecules is a vital component of GRNs, while it has been proved rigorously that the diffusion coefficient of the protein/mRNA acts as a bifurcation parameter and gives rise to a Hopf-bifurcation. In this paper we consider the spatial aspect further by considering the specific location of gene and protein production, showing that there is an optimum range for the distance between an mRNA gene-site and a protein production site in order to achieve oscillations. We first present a model of a well-known GRN, the Hes1 system, and then extend the approach to examine spatio-temporal models of synthetic GRNs e.g. n-gene repressilator and activator-repressor systems. By incorporating the idea of production sites into such models we show that the spatial component is vital to fully understand GRN dynamics.
authors.affiliation: School of Mathematics and Statistics, Mathematical Institute, University of St Andrews, KY16 9SS, United Kingdom.
authors.forename: Cicely K
authors.initials: CK
authors.lastname: Macnamara
authors.affiliation: School of Mathematics and Statistics, Mathematical Institute, University of St Andrews, KY16 9SS, United Kingdom. Electronic address: majc@st-andrews.ac.uk.
authors.forename: Mark Aj
authors.initials: MA
authors.lastname: Chaplain
mesh_terms: D000818:Animals; D003198:Computer Simulation; D004058:Diffusion; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008957:Models, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013045:Species Specificity; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1
keywords: Activator–repressor systems; Hes1 protein; Repressilators; Spatial modelling; Synthetic networks