Every cell must coordinate and regulate thousands of genes in a robust manner to ensure cellular function. Complex gene regulation is needed for most biological processes, such as development, physiological homeostasis, and response to environmental stresses. Networks of genes have evolved to coordinate and integrate biological processes within a cell and subsequently regulate the fate of the organism.
The Walhout lab wishes to understand gene regulatory networks and how these networks adapt to different conditions. We use systems biology approaches to dissect these complex and robust networks. These approaches combine high-quality and large-scale genetic and biochemical data sets and uses computational modeling to integrate the data such that the organizing principles and emergent properties of biological systems are unveiled.
To examine gene regulatory networks we mainly use the model organism round worm Caenorhabditis elegans. 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 eucaryotes. Overall, our research involves two broad areas of biology…read more…
Metabolic network rewiring is the rerouting of metabolism through the use of alternate enzymes to adjust pathway flux and accomplish specific anabolic or catabolic objectives. Here, we report the first characterization of two parallel pathways for the breakdown of the short chain fatty acid propionate in Caenorhabditis elegans. Using genetic interaction mapping, gene co-expression analysis, pathway intermediate quantification and carbon tracing, we uncover a vitamin B12-independent propionate breakdown shunt that is transcriptionally activated on vitamin B12 deficient diets, or under genetic conditions mimicking the human diseases propionic- and methylmalonic acidemia, in which the canonical B12-dependent propionate breakdown pathway is blocked. Our study presents the first example of transcriptional vitamin-directed metabolic network rewiring to promote survival under vitamin deficiency. The ability to reroute propionate breakdown according to B12 availability may provide C. elegans with metabolic plasticity and thus a selective advantage on different diets in the wild.
Watson E, Olin-Sandoval V, Hoy MJ, Li C, Louisse T, Yao V, Mori A, Holdorf AD, Troyanskaya OG, Ralser M, Walhout AJM (2016) Metabolic network rewiring of propionate flux compensates vitamin B12 deficiency in C. elegans. eLife, doi: 10.7554/eLife.17670
University of Massachusetts Medical School Chancellor Michael Collins presenting the Chancellor’s Award for Outstanding Research to Dr. Emma Watson
Citing the profound, insightful, scientific and, in some cases, jovial words of others, Graduate School of Biomedical Sciences Dean Anthony Carruthers, PhD, reminded the crowd assembled in the Albert Sherman Center Cube on Thursday, June 2, to occasionally revisit the fertile grounds of the scientific giants who preceded them.
“Their legacy is the scientific foundation that shapes all we do,” said Dean Carruthers, professor of biochemistry and molecular pharmacology, during the GSBS Celebration of Student Achievement.
Diet-Responsive Gene Networks Rewire Metabolism in the Nematode Caenorhabditis elegans to Provide Robustness Against Vitamin B12 Deficiency
Marian Walhout, PhD, mentor
Dr. Watson is currently a post-doctoral fellow in Stephen Elledge’s lab at Harvard Medical School.
Read more and see other award winners here.
Caenorhabditis elegans is a powerful model to study metabolism and how it relates to nutrition, gene expression, and life history traits. However, while numerous experimental techniques that enable perturbation of its diet and gene function are available, a high-quality metabolic network model has been lacking. Here, we reconstruct an initial version of the C. elegans metabolic network. This network model contains 1,273 genes, 623 enzymes, and 1,985 metabolic reactions and is referred to as iCEL1273. Using flux balance analysis, we show that iCEL1273 is capable of representing the conversion of bacterial biomass into C. elegans biomass during growth and enables the predictions of gene essentiality and other phenotypes. In addition, we demonstrate that gene expression data can be integrated with the model by comparing metabolic rewiring in dauer animals versus growing larvae. iCEL1273 is available at a dedicated website (wormflux.umassmed.edu) and will enable the unraveling of the mechanisms by which different macro- and micronutrients contribute to the animal’s physiology.
Read the Press Release from UMMS.
Yilmaz LS, Walhout AJM (2016) A Caenorhabditis elegans Genome-Scale Metabolic Network Model. Cell Systems 2, 297–311doi: 10.1016/j.cels.2016.04.012
Feedback loops in metabolic network regulation. Click to enlarge.
Metabolic networks are extensively regulated to facilitate tissue-specific metabolic programs and robustly maintain homeostasis in response to dietary changes. Homeostatic metabolic regulation is achieved through metabolite sensing coupled to feedback regulation of metabolic enzyme activity or expression. With a wealth of transcriptomic, proteomic, and metabolomic data available for different cell types across various conditions, we are challenged with understanding global metabolic network regulation and the resulting metabolic outputs. Stoichiometric metabolic network modeling integrated with “omics” data has addressed this challenge by generating nonintuitive, testable hypotheses about metabolic flux rewiring. Model organism studies have also yielded novel insight into metabolic networks. This review covers three topics: the feedback loops inherent in metabolic regulatory networks, metabolic network modeling, and interspecies studies utilizing Caenorhabditis elegans and various bacterial diets that have revealed novel metabolic paradigms.
Watson E, Yilmas LS, Walhout AJ (2015) Understanding Metabolic Regulation at a Systems Level: Metabolite Sensing, Mathematical Predictions, and Model Organisms. Annu. Rev. Genet. 49, 553-575.
December 1 & 2, 2015
This workshop will focus on how we can quantitatively measure and catalog in a computable fashion, all protein-protein interactions and other key interactions in various human cell types. Talks from experts will be complemented by extensive discussions.
Co-sponsored by the Icahn School of Medicine at Mount Sinai and the University of Massachusetts Medical School