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

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.

Network location and clustering of genetic mutations determine chronicity in a stylized model of genetic diseases

“…For biological systems, where the knowledge about interactions of biological entities is more complete than for human cells, e.g., bacteria, it has been shown that the precise interplay of genetic regulation and metabolism installs a balance between robustness to environmental fluctuations and sensitivity to genetic changes 41 – 43 . By adjusting the ratio between AND and OR gates we can continuously tune our model to such a robust or sensitive behaviour.…”

Atlas: automatic modeling of regulation of bacterial gene expression and metabolism using rule-based languages

“…Gene expression regulates metabolism, which, in turn, modulates transcription, translation and degradation rates as well as the activity of transcription factors ( Covert et al , 2008 ). These processes interplay in networks of molecular interactions between DNA, RNA, proteins and metabolites ( Grimbs et al , 2019 ; Hernández-Prieto et al , 2014 ). Here, we aimed to perform the integrative modeling of transcription, translation, regulation of gene expression, metabolism and genome architecture, which is considered a prototype whole-cell model ( Szigeti et al , 2018 ).…”

Computation-guided redesign of promoter specificity of a bacterial RNA polymerase

“…With emerging technologies to synthesize chromosomes from scratch, multiple gene regulation codes can be partitioned and programmed into cells. 1,2 Such a system could have orthogonal regulation encoded in different genomic regions while sharing common core machinery like transcription. 3,4 Gene regulation in bacteria is governed at the global and local levels.…”