Physiologically Shrinking the Solution Space of a Saccharomyces cerevisiae Genome-Scale Model Suggests the Role of the Metabolic Network in Shaping Gene Expression Noise

PLoS One. 2015 Oct 8;10(10):e0139590. doi: 10.1371/journal.pone.0139590. eCollection 2015.

Abstract

Sampling the solution space of genome-scale models is generally conducted to determine the feasible region for metabolic flux distribution. Because the region for actual metabolic states resides only in a small fraction of the entire space, it is necessary to shrink the solution space to improve the predictive power of a model. A common strategy is to constrain models by integrating extra datasets such as high-throughput datasets and C13-labeled flux datasets. However, studies refining these approaches by performing a meta-analysis of massive experimental metabolic flux measurements, which are closely linked to cellular phenotypes, are limited. In the present study, experimentally identified metabolic flux data from 96 published reports were systematically reviewed. Several strong associations among metabolic flux phenotypes were observed. These phenotype-phenotype associations at the flux level were quantified and integrated into a Saccharomyces cerevisiae genome-scale model as extra physiological constraints. By sampling the shrunken solution space of the model, the metabolic flux fluctuation level, which is an intrinsic trait of metabolic reactions determined by the network, was estimated and utilized to explore its relationship to gene expression noise. Although no correlation was observed in all enzyme-coding genes, a relationship between metabolic flux fluctuation and expression noise of genes associated with enzyme-dosage sensitive reactions was detected, suggesting that the metabolic network plays a role in shaping gene expression noise. Such correlation was mainly attributed to the genes corresponding to non-essential reactions, rather than essential ones. This was at least partially, due to regulations underlying the flux phenotype-phenotype associations. Altogether, this study proposes a new approach in shrinking the solution space of a genome-scale model, of which sampling provides new insights into gene expression noise.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Databases, Factual
  • Genome*
  • Metabolic Networks and Pathways*
  • Models, Biological*
  • Phenotype
  • RNA, Messenger / metabolism
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Transcriptome*

Substances

  • RNA, Messenger

Grants and funding

The work was supported by the project from National Natural Science Fund Program (No. 31271917) (http://www.nsfc.gov.cn) and Fundamental Research Funds for the Central Universities (Z109021201). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.