Transcriptomics

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A whole-animal, genome-scale model of transcriptional rewiring of metabolism


ABSTRACT: The regulation of metabolism is vital to any organism. One mechanism of this regulation is by transcriptionally activating or repressing genes encoding metabolic enzymes and transporters. This is used to wire tissue-relevant metabolic networks during development, but also to rewire metabolism upon nutritional or genetic perturbations. While many individual examples of transcriptional regulation of metabolism have been reported, a systems-level study of how metabolic gene expression responds to such perturbations is lacking in any animal. Here, we apply worm perturb-seq (WPS), a high-throughput, whole-animal RNAi/RNA-seq method, on ~900 metabolic genes in the nematode Caenorhabditis elegans, to derive a metabolic gene regulatory network (mGRN) in which the knockdown of 365 metabolic genes is connected to 9,414 differentially expressed genes (DEGs) by more than 110,000 interactions. The mGRN has a highly modular structure in which distinct 22 perturbation clusters connect to 44 co-regulated gene expression programs. We uncover widespread yet highly specific responses in genes associated with stress responses and food digestion, along with various modes of transcriptional changes from simple ‘within pathway’ to complex ‘network coordination’. By integrating the mGRN with metabolic network modeling, we elucidate an underlying designing principle of transcriptional rewiring that leads us to propose a ‘compensation/repression model’ in which high-level, core metabolic functions regulate each other, likely to maintain animal homeostasis.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE253847 | GEO | 2024/11/20

REPOSITORIES: GEO

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