A computational method using differential gene expression to predict altered metabolism of multicellular organisms†

Abstract

Altered metabolism is often identified as a cause or an effect of physiology and pathogenesis. But it is difficult to predict the metabolic flux distributions of multicellular organisms due to the lack of an explicit metabolic objective function. Here we present a computational method which can successfully describe the differences in metabolism between two different conditions on a large scale. By integrating gene expression data with an existing comprehensive reconstruction of the global human metabolic network, we qualitatively predicted significantly differential fluxes without prior knowledge or the rate of metabolite uptake and secretion. Therefore, this method can be applied for both microorganisms and multicellular organisms. Different from traditional enrichment analysis methods and constraint-based models, we consider conditions and interactions within the metabolic network simultaneously. To apply the proposed method, we predicted altered fluxes for E. coli strains and clear cell renal cell carcinoma, while the E. coli strains are growing aerobically in a chemostat with different dilution rates and clear cell renal cell carcinoma is compared with normal kidney cells. Then we map the significantly differential reactions to metabolic subsystems defined in the original metabolic network for ccRCC to observe the altered metabolism. In contrast with existing studies, our results show a high accuracy of the E. coli experiment and a more reasonable prediction of the ccRCC experiment. The method presented here provides a computational approach for the genome-wide study of altered metabolism under pairs of conditions for both microorganisms and multicellular organisms.