Biology subjects

Walhout, A. J.

Publications and source records attributed to Walhout, A. J..

5 recordsLinked to original sources

bioRxiv2024

idh-1 neomorphic mutation confers sensitivity to vitamin B12 via increased dependency on one-carbon metabolism in Caenorhabditis elegans

The isocitrate dehydrogenase neomorphic mutation (idh-1neo) generates increased levels of cellular D-2-hydroxyglutarate (D-2HG), a proposed oncometabolite. However, the physiological effects of increased D-2HG and whether additional metabolic changes occur in the presence of an idh-1neo mutation are not well understood. We created a C. elegans model to study the effects of the idh-1neo mutation in a whole animal. Comparing the phenotypes exhibited by the idh-1neo to{Delta} dhgd-1 (D-2HG dehydrogenase) mutant animals, which also accumulate D-2HG, we identified a specific vitamin B12 diet-dependent vulnerability in idh-1neo mutant animals that leads to increased embryonic lethality. Through a genetic screen we found that impairment of the glycine cleavage system, which generates one-carbon donor units, exacerbates this phenotype. Additionally, supplementation with an alternate source of one-carbon donors suppresses the lethal phenotype. Our results indicate that the idh-1neo mutation imposes a heightened dependency on the one-carbon pool and provides a further understanding how this oncogenic mutation rewires cellular metabolism.

biochemistry↗

bioRxiv2022

Systems-level transcriptional regulation of Caenorhabditis elegans metabolism

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.

systems biology↗

bioRxiv2022

Evolved bacterial resistance to the chemotherapy gemcitabine modulates its efficacy

Drug metabolism by the microbiome can influence anti-cancer treatment success. We previously suggested that chemotherapies with antimicrobial activity can select for adaptations in bacterial drug metabolism that can inadvertently influence the hosts chemoresistance. We demonstrated that evolved resistance against fluoropyrimidine chemotherapy lowered its efficacy in worms feeding on drug-evolved bacteria (Rosener et al., 2020). Here we examine a model system that captures local interactions that can occur in the tumor microenvironment. Gammaproteobacteria colonizing pancreatic tumors can degrade the nucleoside-analog chemotherapy gemcitabine and, in doing so, can increase the tumors chemoresistance. Using a genetic screen in Escherichia coli, we mapped all loss-of-function mutations conferring gemcitabine resistance. Surprisingly, we found that one third of resistance mutations increase or decrease bacterial drug breakdown and therefore can either lower or raise the gemcitabine load in the local environment. Experiments in three E. coli strains revealed that evolved adaptation converged to inactivation of the nucleoside permease NupC, an adaptation that increased the drug burden on co-cultured cancer cells. The two studies provide complementary insights on the potential impact of microbiome adaptation to chemotherapy by showing that bacteria-drug interactions transpire locally and systemically and can influence chemoresistance in the host.

systems biology↗

bioRxiv2021

Chromosome-level reference genomes for two strains of Caenorhabditis briggsae: an improved platform for comparative genomics

The publication of the Caenorhabditis briggsae reference genome in 2003 enabled the first comparative genomics studies between C. elegans and C. briggsae, shedding light on the evolution of genome content and structure in the Caenorhabditis genus. However, despite being widely used, the currently available C. briggsae reference genome is substantially less complete and structurally accurate than the C. elegans reference genome. Here, we used high-coverage Oxford Nanopore long-read and chromosome conformation capture data to generate chromosomally resolved reference genomes for two C. briggsae strains: QX1410, a new reference strain closely related to the laboratory AF16 strain, and VX34, a highly divergent strain isolated in China. We also sequenced 99 recombinant inbred lines (RILs) generated from reciprocal crosses between QX1410 and VX34 to create a recombination map and identify chromosomal domains. Additionally, we used both short- and long-read RNA sequencing (RNA-seq) data to generate high-quality gene annotations. By comparing these new reference genomes to the current reference, we reveal that hyper-divergent haplotypes cover large portions of the C. briggsae genome, similar to recent reports in C. elegans and C. tropicalis. We also show that the genomes of selfing Caenorhabditis species have undergone more rearrangement than their outcrossing relatives, which has biased previous estimates of rearrangement rate in Caenorhabditis. These new genomes provide a substantially improved platform for comparative genomics in Caenorhabditis and narrow the gap between the quality of genomic resources available for C. elegans and C. briggsae.

genomics↗

bioRxiv2018

A Persistence Detector for Metabolic Network Rewiring in an Animal

Biological systems must possess mechanisms that prevent inappropriate responses to spurious environmental signals. Gene regulatory network circuitries known as coherent type 1 feed-forward loops (FFLs) with AND-logic gates have been proposed to function as a persistence detector because it generates a delay in target activation and prevents target induction unless the input signal is sustained. While such a circuit has been found for the L-arabinose utilization system in E. coli, their existence and relevance multicellular organisms has remained unclear. Here, we identify the first persistence detector in an animal that redirects propionate breakdown to a shunt pathway when flux through the canonical propionate breakdown pathway is perturbed. We propose that this mechanism has evolved to ensure the shunt pathway stays off unless propionate accumulation is persistent because the shunt pathway generates highly toxic acrylate. Our study uniquely connects persistence detector circuitry to a physiological response in an animal.

systems biology↗