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2 Publications visible to you, out of a total of 2
Predicting Metabolism from Gene Expression in an Improved Whole-Genome Metabolic Network Model of Danio rerio.

Abstract (Expand)

Zebrafish is a useful modeling organism for the study of vertebrate development, immune response, and metabolism. Metabolic studies can be aided by mathematical reconstructions of the metabolic network … of zebrafish. These list the substrates and products of all biochemical reactions that occur in the zebrafish. Mathematical techniques such as flux-balance analysis then make it possible to predict the possible metabolic flux distributions that optimize, for example, the turnover of food into biomass. The only available genome-scale reconstruction of zebrafish metabolism is ZebraGEM. In this study, we present ZebraGEM 2.0, an updated and validated version of ZebraGEM. ZebraGEM 2.0 is extended with gene-protein-reaction associations (GPRs) that are required to integrate genetic data with the metabolic model. To demonstrate the use of these GPRs, we performed an in silico genetic screening for knockouts of metabolic genes and validated the results against published in vivo genetic knockout and knockdown screenings. Among the single knockout simulations, we identified 74 essential genes, whose knockout stopped growth completely. Among these, 11 genes are known have an abnormal knockout or knockdown phenotype in vivo (partial), and 41 have human homologs associated with metabolic diseases. We also added the oxidative phosphorylation pathway, which was unavailable in the published version of ZebraGEM. The updated model performs better than the original model on a predetermined list of metabolic functions. We also determined a minimal feed composition. The oxidative phosphorylation pathways were validated by comparing with published experiments in which key components of the oxidative phosphorylation pathway were pharmacologically inhibited. To test the utility of ZebraGEM2.0 for obtaining new results, we integrated gene expression data from control and Mycobacterium marinum-infected zebrafish larvae. The resulting model predicts impeded growth and altered histidine metabolism in the infected larvae.

Authors: L. van Steijn, F. J. Verbeek, H. P. Spaink, R. M. H. Merks

Date Published: 20th Jun 2019

Publication Type: Not specified

Reconstruction of Danio rerio metabolic model accounting for subcellular compartmentalisation

Abstract (Expand)

Plant and microbial metabolic engineering is commonly used in the production of functional foods and quality trait improvement. Computational model-based approaches have been used in this important … endeavour. However, to date, fish metabolic models have only been scarcely and partially developed, in marked contrast to their prominent success in metabolic engineering. In this study we present the reconstruction of fully compartmentalised models of the Danio rerio (zebrafish) on a global scale. This reconstruction involves extraction of known biochemical reactions in D. rerio for both primary and secondary metabolism and the implementation of methods for determining subcellular localisation and assignment of enzymes. The reconstructed model (ZebraGEM) is amenable for constraint-based modelling analysis, and accounts for 4,988 genes coding for 2,406 gene-associated reactions and only 418 non-gene-associated reactions. A set of computational validations (i.e., simulations of known metabolic functionalities and experimental data) strongly testifies to the predictive ability of the model. Overall, the reconstructed model is expected to lay down the foundations for computational-based rational design of fish metabolic engineering in aquaculture.

Author: M. Bekaert

Date Published: 14th Nov 2012

Publication Type: Not specified

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