A system-wide network reconstruction of gene regulation and metabolism in Escherichia coli

Genome-scale metabolic models have become a fundamental tool for examining metabolic principles. However, metabolism is not solely characterized by the underlying biochemical reactions and catalyzing enzymes, but also affected by regulatory events. Since the pioneering work of Covert and co-workers as well as Shlomi and co-workers it is debated, how regulation and metabolism synergistically characterize a coherent cellular state. The first approaches started from metabolic models, which were extended by the regulation of the encoding genes of the catalyzing enzymes. By now, bioinformatics databases in principle allow addressing the challenge of integrating regulation and metabolism on a system-wide level. Collecting information from several databases we provide a network representation of the integrated gene regulatory and metabolic system for Escherichia coli, including major cellular processes, from metabolic processes via protein modification to a variety of regulatory events. Besides transcriptional regulation, we also take into account regulation of translation, enzyme activities and reactions. Our network model provides novel topological characterizations of system components based on their positions in the network. We show that network characteristics suggest a representation of the integrated system as three network domains (regulatory, metabolic and interface networks) instead of two. This new three-domain representation reveals the structural centrality of components with known high functional relevance. This integrated network can serve as a platform for understanding coherent cellular states as active subnetworks and to elucidate crossover effects between metabolism and gene regulation. Author summary Networksthe compact representation of systems in terms of nodes and linksare an efficient data structure for biological information. They also allow us to establish relationships between network structure and dynamical function and thus hold the potential of implementing a systems-level view on biological processes. Using the formal language of networks and careful manual curation, we unite information from a range of publicly available databases, in order to provide a metabolic-regulatory network model for the gut bacterium Escherichia coli, which allows us to provide novel topological characterizations of system components based on their positions in the entire network. From the network representation we derive a new partition of the system into three network domains, one predominantly associated with gene regulation, a second, which covers all metabolic processes and a third domain, containing protein interactions and serving as an interface between the two other domains. This has consequences for the topological prediction of the biological relevance of the system components. We discuss specific examples, where this new three-domain representation reveals the structural centrality of components with known high functional relevance. This integrated network can serve as a platform for understanding biological phenomena jointly mediated by gene regulation and metabolism and thus provide insight relevant for genetic and metabolic engineering.