Determining the Control Circuitry of Redox Metabolism at the Genome-Scale
| Autor: | Harish Nagarajan, Bernhard O. Palsson, Joshua A. Lerman, Stephen Federowicz, Byung-Kwan Cho, Ali Ebrahim, Donghyuk Kim, Karsten Zengler |
|---|---|
| Přispěvatelé: | Burkholder, William F |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Anabolism Transcription Genetic Applied Microbiology ved/biology.organism_classification_rank.species Gene regulatory network Biochemistry RNA-POLYMERASE Transcriptional regulation Gene Regulatory Networks Anaerobiosis NETWORK ADAPTATION Genetics (clinical) GENE-EXPRESSION Regulation of gene expression Genetics 0303 health sciences Escherichia coli Proteins Systems Biology Bacterial ARCA Infectious Diseases ESCHERICHIA-COLI Metabolic Pathways ALPHA-SUBUNIT Transcription Oxidation-Reduction Network Analysis TRANSITION Research Article Biotechnology Computer and Information Sciences lcsh:QH426-470 GENETICS Electrons Computational biology Biology Microbiology Electron Transport 03 medical and health sciences Industrial Microbiology Metabolic Networks Affordable and Clean Energy Genetic BACTERIAL TRANSCRIPTION INITIATION Microbial Control Escherichia coli Model organism Molecular Biology Transcription factor Gene Psychological repression Ecology Evolution Behavior and Systematics 030304 developmental biology Regulatory Networks 030306 microbiology ved/biology Human Genome Biology and Life Sciences Computational Biology Gene Expression Regulation Bacterial AEROBIC CONDITIONS lcsh:Genetics Metabolism Gene Expression Regulation Energy Metabolism Developmental Biology Transcription Factors |
| Zdroj: | Federowicz, S, Kim, D, Ebrahim, A, Lerman, J, Nagarajan, H, Cho, B, Zengler, K & Palsson, B 2014, ' Determining the Control Circuitry of Redox Metabolism at the Genome-Scale ', P L o S Genetics, vol. 10, no. 4, e1004264 . https://doi.org/10.1371/journal.pgen.1004264 PLoS Genetics PLoS genetics, vol 10, iss 4 PLoS Genetics, Vol 10, Iss 4, p e1004264 (2014) |
| Popis: | Determining how facultative anaerobic organisms sense and direct cellular responses to electron acceptor availability has been a subject of intense study. However, even in the model organism Escherichia coli, established mechanisms only explain a small fraction of the hundreds of genes that are regulated during electron acceptor shifts. Here we propose a qualitative model that accounts for the full breadth of regulated genes by detailing how two global transcription factors (TFs), ArcA and Fnr of E. coli, sense key metabolic redox ratios and act on a genome-wide basis to regulate anabolic, catabolic, and energy generation pathways. We first fill gaps in our knowledge of this transcriptional regulatory network by carrying out ChIP-chip and gene expression experiments to identify 463 regulatory events. We then interfaced this reconstructed regulatory network with a highly curated genome-scale metabolic model to show that ArcA and Fnr regulate >80% of total metabolic flux and 96% of differential gene expression across fermentative and nitrate respiratory conditions. Based on the data, we propose a feedforward with feedback trim regulatory scheme, given the extensive repression of catabolic genes by ArcA and extensive activation of chemiosmotic genes by Fnr. We further corroborated this regulatory scheme by showing a 0.71 r2 (p Author Summary All heterotrophic organisms must balance the deployment of consumed carbon compounds between growth and the generation of energy. These two competing objectives have been shown, both computationally and experimentally, to exist as the principal dimensions of the function of metabolic networks. Each of these dimensions can also be thought of as the familiar metabolic functions of catabolism, anabolism, and generation of energy. Here we detail how two global transcription factors (TFs), ArcA and Fnr of Escherichia coli that sense redox ratios, act on a genome-wide basis to coordinately regulate these global metabolic functions through transcriptional control of enzyme and transporter levels in changing environments. A model results from the study that shows how global transcription factors regulate global dimensions of metabolism and form a regulatory hierarchy that reflects the structural hierarchy of the metabolic network. |
| Databáze: | OpenAIRE |
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