Co-regulation of metabolic genes is better explained by flux coupling than by network distance

Richard A. Notebaart, Bas Teusink, Roland J. Siezen, Balázs Papp*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

71 Citations (Scopus)


To what extent can modes of gene regulation be explained by systems-level properties of metabolic networks? Prior studies on co-regulation of metabolic genes have mainly focused on graph-theoretical features of metabolic networks and demonstrated a decreasing level of co-expression with increasing network distance, a naïve, but widely used, topological index. Others have suggested that static graph representations can poorly capture dynamic functional associations, e.g., in the form of dependence of metabolic fluxes across genes in the network. Here, we systematically tested the relative importance of metabolic flux coupling and network position on gene co-regulation, using a genome-scale metabolic model of Escherichia coli. After validating the computational method with empirical data on flux correlations, we confirm that genes coupled by their enzymatic fluxes not only show similar expression patterns, but also share transcriptional regulators and frequently reside in the same operon. In contrast, we demonstrate that network distance per se has relatively minor influence on gene co-regulation. Moreover, the type of flux coupling can explain refined properties of the regulatory network that are ignored by simple graph-theoretical indices. Our results underline the importance of studying functional states of cellular networks to define physiologically relevant associations between genes and should stimulate future developments of novel functional genomic tools.

Original languageEnglish
Article numbere26
Pages (from-to)157-163
JournalPLoS Computational Biology
Issue number1
Publication statusPublished - 25 Jan 2008
Externally publishedYes


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