Modeling tissue‐relevant Caenorhabditis elegans metabolism at network, pathway, reaction, and metabolite levels

Abstract

Metabolism is a highly compartmentalized process that provides building blocks for biomass generation during development, homeostasis, and wound healing, and energy to support cellular and organismal processes. In metazoans, different cells and tissues specialize in different aspects of metabolism. However, studying the compartmentalization of metabolism in different cell types in a whole animal and for a particular stage of life is difficult. Here, we present MEtabolic models Reconciled with Gene Expression (MERGE), a computational pipeline that we used to predict tissue‐relevant metabolic function at the network, pathway, reaction, and metabolite levels based on single‐cell RNA‐sequencing (scRNA‐seq) data from the nematode Caenorhabditis elegans. Our analysis recapitulated known tissue functions in C. elegans, captured metabolic properties that are shared with similar tissues in human, and provided predictions for novel metabolic functions. MERGE is versatile and applicable to other systems. We envision this work as a starting point for the development of metabolic network models for individual cells as scRNA‐seq continues to provide higher‐resolution gene expression data.

WormPaths:Caenorhabditis elegansmetabolic pathway annotation and visualization

“…To generate WormPaths, we built on available resources, most notably the iCEL1314 metabolic network model [3], KEGG [6], MetaCyc [7], WormBase [28], and literature searches (Fig 1A). Briefly, we manually curated each of the 1314 genes present in the iCEL1314 model and assigned them to one or more pathway (see methods).…”

“…For example, in glycolysis/gluconeogenesis the interconversion between phosphoenolpyruvate (pep) and oxaloacetate (oaa) is associated with pck-1, pck-2, or pck-3 (Fig 2A). None of these genes is associated with any other reaction and therefore they may function in different conditions or in different tissues [3]. Indeed, at the second larval (L2) stage, two of these three genes show very distinct tissue expression patterns, while the mRNA for the third gene (pck-3) was undetectable (S4 (Fig 2A).…”

“…For instance, the aldehyde dehydrogenase alh-2 is associated with 15 KEGG pathways (Fig 5A). However, in several of these KEGG reactions, alh-2 is associated with one or more isolated reactions that are not connected to iCEL1314 [3] ( Fig 5B). This can be further visualized in the KEGG pantothenate and CoA biosynthesis map from Fig 3A; enzyme EC1.…”

“…Metabolic network models are extremely useful because they can be used with flux balance analysis (FBA) to derive specific insights and hypotheses. For example, gene expression profiling data can be used to gain insight into metabolic network activity at pathway, reaction and metabolite levels under different conditions, or in particular tissues [2][3][4][5].…”

“…To enable more global analyses of C. elegans metabolism, we have previously reconstructed its first genome-scale metabolic network model [2]. The recently updated version of this model includes 1,314 genes, 907 metabolites and 2,230 reactions, and is referred to as iCEL1314 [3]. Information about this network and all the components involved is publicly available on our WormFlux website (http://wormflux.umassmed.edu).…”