A metabolic regulatory network for the Caenorhabditis elegans intestine

Bhattacharya, Sushila; Horowitz, Brent B.; Zhang, Jingyan; Li, Xuhang; Zhang, Hefei; Giese, Gabrielle E.; Holdorf, Amy D.; Walhout, Albertha J.M.

doi:10.1016/j.isci.2022.104688

Cited by 9 publications

(30 citation statements)

References 69 publications

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“…To test this, we used RNAi of 1495 C. elegans metabolic genes to identify genes that increased or decreased drug toxicity when knocked down. These include genes with known metabolic functions that make up the genome-scale iCEL1314 metabolic network model, as well as additional genes predicted to encode metabolic enzymes 30 . We did not find any genes that, upon RNAi knockdown, rendered the animals less sensitive to tamoxifen.…”

Section: Resultsmentioning

confidence: 99%

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Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism

et al. 2022

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Tamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect in Caenorhabditis elegans, which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity in C. elegans, with a three-order of magnitude difference between animals fed Escherichia coli, Comamonas aquatica, and Bacillus subtilis. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals.

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Section: Resultsmentioning

confidence: 99%

“…We tested a collection of 1645 individual E. coli HT115 strains expressing dsRNA against a unique C. elegans metabolic gene 30 . The screens were performed using 96-well plates containing NGM supplemented with tamoxifen, 50 µg/mL ampicillin, and 2 mM IPTG.…”

Section: Methodsmentioning

confidence: 99%

Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism

et al. 2022

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show abstract

“…To test this, we used RNAi of 1,495 C. elegans metabolic genes to identify genes that increased or decreased drug toxicity when knocked down. These include genes with known metabolic functions that make up the genome-scale iCEL1314 metabolic network model, as well as additional genes predicted to encode metabolic enzymes 29 . We did not find any genes that, upon RNAi knockdown, rendered the animals less sensitive to tamoxifen.…”

Section: Resultsmentioning

confidence: 99%

“…We tested a collection of 1,645 individual E. coli HT115 strains expressing dsRNA against a unique C. elegans metabolic gene 29 . The screens were performed using 96- well plates containing NGM supplemented with tamoxifen, 50 µg/mL ampicillin, and 2 mM IPTG.…”

Section: Methodsmentioning

confidence: 99%

Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism

Diot

García-González

Vieira

et al. 2021

Preprint

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SUMMARYTamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect in Caenorhabditis elegans, which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity in C. elegans, with a three-order of magnitude difference between animals fed Escherichia coli, Comamonas aquatica, and Bacillus subtilis. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals.

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“…By using flux balance analysis (FBA), iCEL1314 can be used to gain insight into the metabolic state of C. elegans during different nutritional conditions or in different tissues. An additional set of metabolic genes has been predicted based on homology with known metabolic enzymes in other organisms or based on the presence of domains found in metabolic enzymes (Bhattacharya et al, 2022; Yilmaz and Walhout, 2016). However, these genes have not been incorporated into the iCEL1314 model because they are not yet annotated to known metabolic reactions or because the reactions they are annotated to cannot yet be connected to the model.…”

Section: Introductionmentioning

confidence: 99%

Systems-level transcriptional regulation ofCaenorhabditis elegansmetabolism

Walhout

Nanda

Jacques

et al. 2022

Preprint

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Metabolism is precisely 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 more than 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 sub-pathways in an unbiased manner. Using a large gene expression compendium, we determine the conditions where sub-pathways 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.

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A metabolic regulatory network for the Caenorhabditis elegans intestine

Cited by 9 publications

References 69 publications

Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism

Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism

Bacterial diet modulates tamoxifen-induced death via host fatty acid metabolism

Systems-level transcriptional regulation ofCaenorhabditis elegansmetabolism

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