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

TL;DR

This paper constructs a comprehensive system-wide network model of gene regulation and metabolism in Escherichia coli, integrating multiple cellular processes to better understand cellular states and component interactions.

Contribution

It provides the first integrated network representation of gene regulation and metabolism in E. coli, including various regulatory layers and a novel three-domain topological framework.

Findings

Network components with high functional relevance are centrally located.

The system can be represented as three interconnected network domains.

The model offers insights into crossover effects between regulation and metabolism.

Abstract

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.