analysing gcn4 translational control in yeast by stochastic chemical kinetics modelling and simulation分析gcn4平移控制酵母通过随机化学动力学建模和仿真.pdfVIP

You et al. BMC Systems Biology 2011, 5:131 /1752-0509/5/131 RESEARCH ARTICLE Open Access Analysing GCN4 translational control in yeast by stochastic chemical kinetics modelling and simulation 1,4 2 1,2 2 1,3* Tao You , Ian Stansfield , M Carmen Romano , Alistair JP Brown and George M Coghill Abstract Background: The yeast Saccharomyces cerevisiae responds to amino acid starvation by inducing the transcription factor Gcn4. This is mainly mediated via a translational control mechanism dependent upon the translation initiation eIF2·GTP·Met-tRNAiMet ternary complex, and the four short upstream open reading frames (uORFs) in its 5’ mRNA leader. These uORFs act to attenuate GCN4 mRNA translation under normal conditions. During amino acid starvation, levels of ternary complex are reduced. This overcomes the GCN4 translation attenuation effect via a scanning/reinitiation control mechanism dependent upon uORF spacing. Results: Using published experimental data, we have developed and validated a probabilistic formulation of GCN4 translation using the Chemical Master Equation (Model 1). Model 1 explains GCN4 translation’s nonlinear dependency upon uORF placements, and predicts that an as yet unidentified factor, which was proposed to regulate GCN4 translation under some conditions, only has pronounced effects upon GCN4 translation when intercistronic distances are unnaturally short. A simpler Model 2 that does not include this unidentified factor could well represent the regulation of a natural GCN4 mRNA. Using parameter values optimised for this algebraic Model 2, we performed stochastic simulations by Gillespie algorithm to investigate the distribution of ribosomes in different sections of GCN4 mRNA u