The regulation of metabolism is vital to any organism and can be achieved by transcriptionally activating or repressing metabolic genes1-3. Although many examples of transcriptional metabolic rewiring have been reported4, a systems-level study of how metabolism is rewired in response to metabolic perturbations is lacking in any animal. Here we apply Worm Perturb-Seq (WPS)-a high-throughput method combining whole-animal RNA-interference and RNA-sequencing5-to around 900 metabolic genes in the nematode Caenorhabditis elegans. We derive a metabolic gene regulatory network (mGRN) in which 385 perturbations are connected to 9,414 genes by more than 110,000 interactions. The mGRN has a highly modular structure in which 22 perturbation clusters connect to 44 gene expression programs. The mGRN reveals different modes of transcriptional rewiring from simple reaction and pathway compensation to rerouting and more complex network coordination. Using metabolic network modelling, we identify a design principle of transcriptional rewiring that we name the compensation-repression (CR) model. The CR model explains most transcriptional responses in metabolic genes and reveals a high level of compensation and repression in five core metabolic functions related to energy and biomass. We provide preliminary evidence that the CR model may also explain transcriptional metabolic rewiring in human cells.
© 2025. The Author(s), under exclusive licence to Springer Nature Limited.