title: Integration of time-resolved transcriptomics data with flux-based methods reveals stress-induced metabolic adaptation in Escherichia coli.
abstract: BACKGROUND
  Changes in environmental conditions require temporal effectuation of different metabolic pathways in order to maintain the organisms' viability but also to enable the settling into newly arising conditions. While analyses of robustness in biological systems have resulted in the characterization of reactions that facilitate homeostasis, temporal adaptation-related processes and the role of cellular pathways in the metabolic response to changing conditions remain elusive.
  
  
  RESULTS
  Here we develop a flux-based approach that allows the integration of time-resolved transcriptomics data with genome-scale metabolic networks. Our framework uses bilevel optimization to extract temporal minimal operating networks from a given large-scale metabolic model. The minimality of the extracted networks enables the computation of elementary flux modes for each time point, which are in turn used to characterize the transitional behavior of the network as well as of individual reactions. Application of the approach to the metabolic network of Escherichia coli in conjunction with time-series gene expression data from cold and heat stress results in two distinct time-resolved modes for reaction utilization-constantly active and temporally (de)activated reactions. These patterns contrast the processes for the maintenance of basic cellular functioning and those required for adaptation. They also allow the prediction of reactions involved in time- and stress-specific metabolic response and are verified with respect to existing experimental studies.
  
  
  CONCLUSIONS
  Altogether, our findings pinpoint the inherent relation between the systemic properties of robustness and adaptability arising from the interplay of metabolic network structure and changing environment.
authors.affiliation: Systems Biology and Mathematical Modeling Group, Max-Planck-Institute of Molecular Plant Physiology, 14476 Potsdam, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Töpfer
authors.forename: Szymon
authors.initials: S
authors.lastname: Jozefczuk
authors.forename: Zoran
authors.initials: Z
authors.lastname: Nikoloski
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D003080:Cold Temperature; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D023281:Genomics; D018869:Heat-Shock Response / Q000235:genetics; D053858:Metabolic Networks and Pathways; D013312:Stress, Physiological / Q000235:genetics*; D013997:Time Factors