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From Steady State to Kinetics Glucose Transport Regulatory Network in S. cerevisiae as a case study Sooraj Kuttykrishnan Brent Lab Center For Genome Sciences Washington University in St. Louis 29 October 2008 Goals • To model and parameterize each component in the network individually. ― To model and parameterize the promoter region of each individual gene. • To predict and test steady state levels and time course of various species in the network. Model Framework • Each regulatory interaction is modeled using an appropriate differential equation. • The system is assumed to be well mixed. • mRNA and protein degradation rates are assumed to be constant. • Stochastic variations are ignored. • • • Qualitative properties are well studied, but kinetics is poorly understood. Number of genes and their regulators is relatively small. Saccharomyces cerevisiae is genetically tractable. Transcription DNA TF1, TF2 Translation mRNA1 + DNA mRNA1 mRNA1 + Protein1 1. Holstege FC et al. 1998, Cell., Vol. 95, pp. 717-728. 2. Yulei Wang et al. 2002 , Proc Natl Acad Sci U S A., Vol. 99, pp. 5860–5865. 3. Belle A et al. 2006, Proc Natl Acad Sci U S A., Vol. 103, pp. 13004-9. 4. Reifenberger E et al. 1997, Eur J Biochem , Vol. 245, pp. 324 -333 Hi Glucose Low Glucose Glucose Rgt2 Snf3 Hxt2,3,4 Glucose metabolism Glucose signal Snf1 Std1 Mth1 Rgt1 HXT2,HXT4 HXT1,HXT3 STD1 MIG2 Mig1 Mig2 SUC2 et al. SNF3 MTH1 MIG1 Topology Is Important WT(2% Glu) ΔRGT1 (2% Gal) Steady State Predictions Predicted Observed • HXT4 was observed to be induced in 0.1% Glucose using β- galactosidase assays. • Long half life of LacZ impedes observation of the fall in HXT4 levels. Conclusions • Modelled and parameterized individual components of the network independently. ― Useful to predict kinetics of rewirings. • Model generated novel and testable hypotheses. ― Steady state predictions are in good agreement with observations. Acknowledgements • Brent Lab • Johnston Lab Michael Brent Jeff Sabina Laura Langton Mark Johnston Brian Haynes
