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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Blog Post: Working together during the COVID-19 pandemic, a silver lining in a trying time

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Dr. Walhout recently wrote a post on the motivations of and the process behind our WormPaths paper (in press at Genetics). This post is featured on the Genetics Society of America “Genes to Genomes” blog. Below is an excerpt.

“Massachusetts, March 2020: The early days of the COVID-19 pandemic that would profoundly affect us all. Labs shut down abruptly, assay trials were disrupted, some experiments in progress were thrown out. Now what? With pipettes unused on the bench and the foreseeable future unclear, how long would this take? A week or two? Oh, how naïve we were. Many labs pivoted to do research on the new virus, leading to many papers, demonstrating that publishing doesn’t have to take months. But I digress… When the lockdown started, I immediately thought my lab could use this time to work on a project that I always wanted to start but never seemed to have the time for…” continued on the blog…

WormPaths: Caenorhabditis elegans metabolic pathway annotation and visualization

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In our group, we aim to understand metabolism in the nematode Caenorhabditis elegans and its relationships with gene expression, physiology, and the response to therapeutic drugs. Visualization of the metabolic pathways that comprise the metabolic network is extremely useful for interpreting a wide variety of experiments. Detailed annotated metabolic pathway maps for C. elegans are mostly limited to pan-organismal maps, many with incomplete or inaccurate pathway and enzyme annotations. Here, we present WormPaths, which is composed of two parts: (1) the careful manual annotation of metabolic genes into pathways, categories, and levels, and (2) 62 pathway maps that include metabolites, metabolite structures, genes, reactions, and pathway connections between maps. These maps are available on the WormFlux website. We show that WormPaths provides easy-to-navigate maps and that the different levels in WormPaths can be used for metabolic pathway enrichment analysis of transcriptomic data. In the future, we envision further developing these maps to be more interactive, analogous to road maps that are available on mobile devices.

WormPaths workflow
Galactose Metabolism (click to enlarge)

Walker MD*, Giese GE*, Holdorf AD*, Bhattacharya S, Diot C, García-González AP, Horowitz B, Lee YU, Leland T, Li X, Mirza Z, Na H, Nanda S, Ponomarova O, Zhang H, Zhang J, Yilmaz LS, Walhout AJM. (2021). WormPaths: Caenorhabditis elegans metabolic pathway annotation and visualization. Genetics, In press.

Modeling tissue‐relevant Caenorhabditis elegans metabolism at network, pathway, reaction, and metabolite levels

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Yilmaz et al. featured on the October cover of Molecular Systems Biology

Metabolism is a highly compartmentalized process that provides building blocks for biomass generation during development, homeostasis, and wound healing, and energy to support cellular and organismal processes. In metazoans, different cells and tissues specialize in different aspects of metabolism. However, studying the compartmentalization of metabolism in different cell types in a whole animal and for a particular stage of life is difficult. Here, we present MEtabolic models Reconciled with Gene Expression (MERGE), a computational pipeline that we used to predict tissue‐relevant metabolic function at the network, pathway, reaction, and metabolite levels based on single‐cell RNA‐sequencing (scRNA‐seq) data from the nematode Caenorhabditis elegans. Our analysis recapitulated known tissue functions in C. elegans, captured metabolic properties that are shared with similar tissues in human, and provided predictions for novel metabolic functions. MERGE is versatile and applicable to other systems. We envision this work as a starting point for the development of metabolic network models for individual cells as scRNA‐seq continues to provide higher‐resolution gene expression data.

Yilmaz LS, Li X, Nanda S, Fox B, Schroeder F, Walhout AJM. (2020). Modeling tissue‐relevant Caenorhabditis elegans metabolism at network, pathway, reaction, and metabolite levels. Mol Syst Biol 16:e9649.

C. elegans methionine/S-adenosylmethionine cycle activity is sensed and adjusted by a nuclear hormone receptor

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Vitamin B12 is an essential micronutrient that functions in two metabolic pathways: the canonical propionate breakdown pathway and the methionine/S-adenosylmethionine (Met/SAM) cycle. In Caenorhabditis elegans, low vitamin B12, or genetic perturbation of the canonical propionate breakdown pathway results in propionate accumulation and the transcriptional activation of a propionate shunt pathway. This propionate-dependent mechanism requires nhr-10 and is referred to as ‘B12-mechanism-I’. Here, we report that vitamin B12 represses the expression of Met/SAM cycle genes by a propionate-independent mechanism we refer to as ‘B12-mechanism-II’. This mechanism is activated by perturbations in the Met/SAM cycle, genetically or due to low dietary vitamin B12. B12-mechanism-II requires nhr-114 to activate Met/SAM cycle gene expression, the vitamin B12 transporter, pmp-5, and adjust influx and efflux of the cycle by activating msra-1 and repressing cbs-1, respectively. Taken together, Met/SAM cycle activity is sensed and transcriptionally adjusted to be in a tight metabolic regime.

Giese GE, Walker MD, Ponomarova O, Zhang H, Li X, Minevich G, Walhout AJM. (2020) C. elegans methionine/S-adenosylmethionine cycle activity is sensed and adjusted by a nuclear hormone receptor. eLife 9:e60259.

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.