Systems‐level transcriptional regulation of Caenorhabditis elegans metabolism

Metabolism is controlled to ensure organismal development and homeostasis. Several mechanisms regulate metabolism, including allosteric control and transcriptional regulation of metabolic enzymes and transporters. So far, metabolism regulation has mostly been described for individual genes and pathways, and the extent of transcriptional regulation of the entire metabolic network remains largely unknown. Here, we find that three‐quarters of all metabolic genes are transcriptionally regulated in the nematode Caenorhabditis elegans . We find that many annotated metabolic pathways are coexpressed, and we use gene expression data and the iCEL1314 metabolic network model to define coregulated subpathways in an unbiased manner. Using a large gene expression compendium, we determine the conditions where subpathways exhibit strong coexpression. Finally, we develop “WormClust,” a web application that enables a gene‐by‐gene query of genes to view their association with metabolic (sub)‐pathways. Overall, this study sheds light on the ubiquity of transcriptional regulation of metabolism and provides a blueprint for similar studies in other organisms, including humans. Synopsis Systems‐level analyses in C. elegans show widespread transcriptional regulation of metabolic genes, coexpression of metabolic (sub)‐pathways, and activation/repression conditions of (sub)‐pathways. Metabolic genes are transcriptionally regulated at a similar proportion as non‐metabolic genes. Metabolic genes exhibit more transcriptional regulation in tissues than during development. Metabolic pathways are frequently coexpressed. A web application tool, WormClust http://wormflux.umassmed.edu/WormClust/wormclust.php , helps researchers find metabolic genes that are co‐expressed with a query gene. Graphical Abstract Systems‐level analyses in C. elegans show widespread transcriptional regulation of metabolic genes, coexpression of metabolic (sub)‐pathways, and activation/repression conditions of (sub)‐pathways.