Accession Number : ADA598557


Title :   Bridging the Gap between Gene Expression and Metabolic Phenotype via Kinetic Models


Descriptive Note : Journal article


Corporate Author : BIOTECHNOLOGY HIGH PERFORMANCE COMPUTING SOFTWARE APPLICATIONS INST FREDERICK MD


Personal Author(s) : Vital-Lopez, Francisco G ; Wallqvist, Anders ; Reifman, Jaques


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a598557.pdf


Report Date : 22 Jul 2013


Pagination or Media Count : 18


Abstract : Despite the close association between gene expression and metabolism, experimental evidence shows that gene expression levels alone cannot predict metabolic phenotypes, indicating a knowledge gap in our understanding of how these processes are connected. Here, we present a method that integrates transcriptome, fluxome, and metabolome data using kinetic models to create a mechanistic link between gene expression and metabolism. We developed a modeling framework to construct kinetic models that connect the transcriptional and metabolic responses of a cell to exogenous perturbations. The framework allowed us to avoid extensive experimental characterization, literature mining, and optimization problems by estimating most model parameters directly from fluxome and transcriptome data. We applied the framework to investigate how gene expression changes led to observed phenotypic alterations of Saccharomyces cerevisiae treated with weak organic acids (i.e., acetate, benzoate, propionate, or sorbate) and the histidine synthesis inhibitor 3-aminotriazole under steady-state conditions. We found that the transcriptional response led to alterations in yeast metabolism that mimicked measured metabolic fluxes and concentration changes. Further analyses generated mechanistic insights of how S. cerevisiae responds to these stresses. In particular, these results suggest that S. cerevisiae uses different regulation strategies for responding to these insults: regulation of two reactions accounted for most of the tolerance to the four weak organic acids, whereas the response to 3-aminotriazole was distributed among multiple reactions. Moreover, we observed that the magnitude of the gene expression changes was not directly correlated with their effect on the ability of S. cerevisiae to grow under these treatments. In addition, we identified another potential mechanism of action of 3-aminotriazole associated with the depletion of tetrahydrofolate.


Descriptors :   *GENE EXPRESSION , *METABOLISM , BIOMASS , CELLS(BIOLOGY) , CONCENTRATION(COMPOSITION) , HISTIDINE , KINETICS , ORGANIC ACIDS , PERTURBATIONS , STARVATION , YEASTS


Subject Categories : Biochemistry
      Genetic Engineering and Molecular Biology
      Anatomy and Physiology


Distribution Statement : APPROVED FOR PUBLIC RELEASE