title: Automatic generation of predictive dynamic models reveals nuclear phosphorylation as the key Msn2 control mechanism.
abstract: Predictive dynamical models are critical for the analysis of complex biological systems. However, methods to systematically develop and discriminate among systems biology models are still lacking. We describe a computational method that incorporates all hypothetical mechanisms about the architecture of a biological system into a single model and automatically generates a set of simpler models compatible with observational data. As a proof of principle, we analyzed the dynamic control of the transcription factor Msn2 in Saccharomyces cerevisiae, specifically the short-term mechanisms mediating the cells' recovery after release from starvation stress. Our method determined that 12 of 192 possible models were compatible with available Msn2 localization data. Iterations between model predictions and rationally designed phosphoproteomics and imaging experiments identified a single-circuit topology with a relative probability of 99% among the 192 models. Model analysis revealed that the coupling of dynamic phenomena in Msn2 phosphorylation and transport could lead to efficient stress response signaling by establishing a rate-of-change sensor. Similar principles could apply to mammalian stress response pathways. Systematic construction of dynamic models may yield detailed insight into nonobvious molecular mechanisms.
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, 4058 Basel, Switzerland. mikael.sunnaker@bsse.ethz.ch
authors.forename: Mikael
authors.initials: M
authors.lastname: Sunnåker
authors.forename: Elias
authors.initials: E
authors.lastname: Zamora-Sillero
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dechant
authors.forename: Christina
authors.initials: C
authors.lastname: Ludwig
authors.forename: Alberto Giovanni
authors.initials: AG
authors.lastname: Busetto
authors.forename: Andreas
authors.initials: A
authors.lastname: Wagner
authors.forename: Joerg
authors.initials: J
authors.lastname: Stelling
mesh_terms: D019295:Computational Biology / Q000379:methods*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000502:physiology; D040901:Proteomics / Q000379:methods; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D049490:Systems Biology / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C081935:MSN2 protein, S cerevisiae; D010750:Phosphoproteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors