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Welcome to the Walhout Lab

Walhout Lab Posted on April 14, 2020 by adminApril 14, 2020

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

read more…

Posted in Welcome

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

Walhout Lab Posted on October 6, 2020 by adminOctober 7, 2020

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.

Posted in Publication | Tagged Ascaroside Biosynthesis, Caenorhabditis elegans, iCEL1314, Metabolic Flux, Metabolism, scRNA-seq

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

Walhout Lab Posted on October 5, 2020 by adminOctober 7, 2020

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.

Posted in Publication | Tagged Caenorhabditis elegans, Met/SAM cycle, NHR-114, Propionate, Vitamin B12

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

Walhout Lab Posted on August 28, 2020 by adminSeptember 14, 2020

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.

 

Posted in Publication | Tagged Caenorhabditis elegans, GWAS, Inborn Errors of Metabolism, Propionate, Quantitative Trait Loci

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

Walhout Lab Posted on December 9, 2019 by adminSeptember 14, 2020

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.

Posted in Publication | Tagged Caenorhabditis elegans, Gene Ontology, Method

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

Walhout Lab Posted on September 5, 2019 by adminSeptember 5, 2019

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.

Posted in Review | Tagged Caenorhabditis elegans, Chemotherapeutics, Drugs, Microbiota

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

Walhout Lab Posted on August 23, 2019 by adminSeptember 14, 2020

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.

Posted in Publication | Tagged Caenorhabditis elegans, E. coli, Flux Balance Analysis, Iron, Reactive Oxygen Species

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Marian Walhout, Ph.D.
The Maroun Semaan Chair in Biomedical Research
Co-Director, Program in Systems Biology
Professor, Program in Molecular Medicine

University of Massachusetts Medical School
Albert Sherman Center, Room 5.1051
386 Plantation St.
Worcester, MA 01605
E-mail: Marian Walhout

Missy Gardella, Assistant to Dr. Walhout
Albert Sherman Center, Room 5.1053
Phone: 508-856-3601
Fax: 508-856-2105

Lab Phone: 508-856-4367

News/Events

October 6, 2020
Modeling tissue‐relevant Caenorhabditis elegans metabolism at network, pathway, reaction, and metabolite levels published in Molecular Systems Biology

October 5, 2020
C. elegans methionine/S-adenosylmethionine cycle activity is sensed and adjusted by a nuclear hormone receptor published in eLife

August 28, 2020
Natural variation in a glucuronosyltransferase modulates propionate sensitivity in a C. elegans propionic acidemia model published in PLoS Genetics

February 3, 2020
Welcome to rotation student Nick Harper!

December 6, 2019
WormCat: An online tool for annotation and visualization of Caenorhabditis elegans genome-scale data published in Genetics

November 16, 2019
Welcome to rotation student Tom Leland!

September 16-18, 2019
CCSB/PSB Retreat, Beauport Hotel, Gloucester, MA

September 5, 2019
C. elegans and its bacterial diet: An interspecies model to explore the effects of microbiota on drug response published in Drug Discovery Today: Disease Models

August 20, 2019
A delicate balance between bacterial iron and reactive oxygen species supports optimal C. elegans development published in Cell Host & Microbe

July 1, 2019
Welcome to our summer interns: Hailey Doyle a senior at Worcester Technical High School, and Isabel Silverman a recent graduate of Acton-Boxborough Regional High School!

June 20-24, 2019
22nd International C. elegans Conference University of California, Los Angeles. Poster presentations by Sushila Bhattacharya (June 22), Brent Horowitz (June 22), Yan Zhang (June 22) and Zeynep Mirza (June 23). Oral presentation by Safak Yilmaz (June 23).

May 15, 2019
Congratulations to doctoral candidate Shivani Nanda on passing her qualifying exam!

April 30, 2019
Congratulations to Dr. Aurian Garcia-Gonzalez on successfully defending her doctoral dissertation!

April 19
Congratulations to WPI senior Akshaye Shah on winning second prize for his poster “High Throughput Screening in Caenorhabditis elegans” about his research for his Major Qualifying Project! Akshaye was supervised by graduate student Brent Horowitz. Great job!

April 8, 2019
Congratulations to doctoral candidate Xuhang Li on passing his qualifying exam!

April 5, 2019
Welcome to rotation student Alexander Park!

March 13, 2019
Congratulations to doctoral candidate Gabrielle Giese for passing her qualifying exam!

March 12, 2019
Transcriptional regulation of metabolic flux: a C. elegans perspective published in Current Opinion in Systems Biology

February 19, 2019
Welcome to post-doctoral fellow Hefei Zhang!

January 8, 2019
A persistence detector for metabolic network rewiring in an animal published in Cell Reports

November 19, 2018
Welcome to Visiting Scholar Rui Gao!

November 19, 2018
Welcome rotation student Vinita Chaudhari!

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