Welcome to the Walhout Lab

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The Structure, Function and Evolution of Biological Networks

In the Walhout lab we aim to understand how biological networks are organized, how their organization enables function, and how these networks evolve. Our main focus is on the gene regulatory networks that control proper gene expression, and on metabolic networks that provide building blocks and energy to support organism development, growth, wound healing, homeostasis, and response to nutritional, environmental and therapeutic inputs. We are particularly interested in the communication between metabolic and gene regulatory networks to ask important questions that navigate both broad systems-level as well as deep mechanistic biological processes. We mainly use the roundworm Caenorhabditis elegans as a model system. Worms are highly adaptable, easy to manipulate, and have many analogs in human genetics. Furthermore, there are many genetic tools and worm-specific techniques that are not available for studying “higher” eukaryotes. Overall, our research involves three broad areas in systems biology:

1: NETWORK STRUCTURE, FUNCTION AND EVOLUTION
2: TISSUE-RELEVANT NETWORKS
3: HOST-MICROBIOTA INTERACTIONS IN NUTRITION AND DRUG RESPONSE

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Natural variation in a glucuronosyltransferase modulates propionate sensitivity in a C. elegans propionic acidemia model

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Natural variation in propionate sensitivity in 12 genetically diverse C. elegans strains.

Mutations in human metabolic genes can lead to rare diseases known as inborn errors of human metabolism. For instance, patients with loss-of-function mutations in either subunit of propionyl-CoA carboxylase suffer from propionic acidemia because they cannot catabolize propionate, leading to its harmful accumulation. Both the penetrance and expressivity of metabolic disorders can be modulated by genetic background. However, modifiers of these diseases are difficult to identify because of the lack of statistical power for rare diseases in human genetics. Here, we use a model of propionic acidemia in the nematode Caenorhabditis elegans to identify genetic modifiers of propionate sensitivity. Using genome-wide association (GWA) mapping across wild strains, we identify several genomic regions correlated with reduced propionate sensitivity. We find that natural variation in the putative glucuronosyltransferase GLCT-3, a homolog of human B3GAT, partly explains differences in propionate sensitivity in one of these genomic intervals. We demonstrate that loss-of-function alleles in glct-3 render the animals less sensitive to propionate. Additionally, we find that C. elegans has an expansion of the glct gene family, suggesting that the number of members of this family could influence sensitivity to excess propionate. Our findings demonstrate that natural variation in genes that are not directly associated with propionate breakdown can modulate propionate sensitivity. Our study provides a framework for using C. elegans to characterize the contributions of genetic background in models of human inborn errors in metabolism.

Na H, Zdraljevic S, Tanny RE, Walhout AJM, Andersen EC (2020). Natural variation in a glucuronosyltransferase modulates propionate sensitivity in a C. elegans propionic acidemia model. PLoS Genet 16(8):e1008984.

 

WormCat: An online tool for annotation and visualization of Caenorhabditis elegans genome-scale data

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Tissue-specific gene expression as analyzed by WormCat.

The emergence of large gene expression datasets has revealed the need for improved tools to identify enriched gene categories and visualize enrichment patterns. While Gene Ontogeny (GO) provides a valuable tool for gene set enrichment analysis, it has several limitations. First, it is difficult to graph multiple GO analyses for comparison. Second, genes from some model systems are not well represented. For example, around 30% of Caenorhabditis elegans genes are missing from the analysis in commonly used databases. To allow categorization and visualization of enriched C. elegans gene sets in different types of genome-scale data, we developed WormCat, a web-based tool that uses a near-complete annotation of the C. elegans genome to identify co-expressed gene sets and scaled heat map for enrichment visualization. We tested the performance of WormCat using a variety of published transcriptomic datasets and show that it reproduces major categories identified by GO. Importantly, we also found previously unidentified categories that are informative for interpreting phenotypes or predicting biological function. For example, we analyzed published RNA-seq data from C. elegans treated with combinations of lifespan-extending drugs where one combination paradoxically shortened lifespan. Using WormCat, we identified sterol metabolism as a category that was not enriched in the single or double combinations but emerged in a triple combination along with the lifespan shortening. Thus, WormCat identified a gene set with potential phenotypic relevance not found with previous GO analysis. In conclusion, WormCat provides a powerful tool for the analysis and visualization of gene set enrichment in different types of C. elegans datasets.

Holdorf AD, Higgins DP, Hart AC, Boag PR, Pazour GJ, Walhout AJM, Walker AK. (2020). WormCat: An Online Tool for Annotation and Visualization of Caenorhabditis elegans Genome-Scale Data. Genetics 214, 279-94.

C. elegans and its bacterial diet: An interspecies model to explore the effects of microbiota on drug response

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Our body is inhabited by a large community of microorganisms referred to as our microbiota that influences almost all aspects of human physiology, including the response to thereapeutic drugs. Drugs can affect microbiota composition and the microbiota can modulate the drug response in the host. A major challenge is to determine which bacteria affect the response to which drugs, and to elucidate the mechanisms involved. Here, we discuss the emergence of the nematode Caenorhabditis elegans and its bacterial diet as an interspecies model system with which the effects of bacteria on the drug response in the host can be studied both at broad systems and at deep mechanistic levels. We will discuss the strengths and limitations of this system and will present future perspectives.

Diot C, Garcia-Gonzalez AP, Walhout AJM (2019). C. elegans and its bacterial diet: An interspecies model to explore the effects of microbiota on drug response. Drug Discovery Today: Disease Models.

A delicate balance between bacterial iron and reactive oxygen species supports optimal C. elegans development

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Highlights

  • A screen of E. coli mutants reveals bacterial genes essential for C. elegans development
  • This developmental delay can be rescued by anti-oxidants or iron supplementation
  • Low bacterial iron raises ROS production likely triggering oxidative stress in C. elegans

Summary

Iron is an essential micronutrient for all forms of life; low levels of iron cause human disease, while too much iron is toxic. Low iron levels induce reactive oxygen species (ROS) by disruption of the heme and iron-sulfur cluster-dependent electron transport chain (ETC). To identify bacterial metabolites that affect development, we screened the Keio Escherichia coli collection and uncovered 244 gene deletion mutants that slow Caenorhabditis elegans development. Several of these genes encode members of the ETC cytochrome bo oxidase complex, as well as iron importers. Surprisingly, either iron or anti-oxidant supplementation reversed the developmental delay. This suggests that low bacterial iron results in high bacterial ROS and vice versa, which causes oxidative stress in C. elegans that subsequently impairs mitochondrial function and delays development. Our data indicate that the bacterial diets of C. elegans provide precisely tailored amounts of iron to support proper development.

Featured on the Chinese life sciences and medical platform BioArt (in Mandarin).

Zhang J, Li X, Olmedo M, Holdorf AD, Shang Y, Artal-Sanz M, Yilmaz LS, Walhout AJM. (2019). A Delicate Balance between Bacterial Iron and Reactive Oxygen Species Supports Optimal C. elegans Development. Cell Host Microbe 26, 400-411.

Congratulations Dr. Garcia-Gonzalez!

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Congratulations to Dr. Aurian P. Garcia-Gonzalez on successfully defending her doctoral dissertation titled, “C. elegans as a model for host-microbe-drug interactions.” Dr. Garcia-Gonzalez will return to medical school next month, and will complete her MD degree in 2021. Great job Auri!

Transcriptional regulation of metabolic flux: a C. elegans perspective

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Metabolic reactions form the basis of life to generate biomass, produce energy and eliminate waste. Together, metabolic reactions function in the context of a highly interconnected metabolic network. Flux through this network needs to be adaptable depending on nutrient availability or metabolite buildup. Metabolic flux can be changed by different regulatory mechanisms, including the allosteric regulation of metabolic enzyme activity by small molecules, and by changes in metabolic gene expression. For the transcriptional control of metabolic genes to happen accurately, the metabolic status of the system needs to be relayed to the regulators of gene expression, such as transcription factors (TFs). While allosteric regulation of metabolic enzymes can only be studied for individual proteins, the transcriptional control of metabolism can increasingly be examined at a systems, or network level. Here, we discuss recent studies regarding the interplay between metabolic and gene regulatory networks using the nematode Caenorhabditis elegans. We discuss why C. elegans provides an elegant model system for studying the transcriptional regulation of metabolism and describe recent insights into its gene regulatory and metabolic networks. We then describe a recently discovered mechanism by which the buildup of a cellular metabolite can transcriptionally rewire metabolism. Finally, we discuss the future challenge of integrating large transcriptomic, proteomic and metabolomic datasets to fully understand the transcriptional regulation of metabolic flux.

Giese GE, Nanda S, Holdorf AD, Walhout AJM. (2019) Transcriptional regulation of metabolic flux: a C. elegans perspective. Curr Opin Syst Biol 15, 12-18.