What we eat greatly influences how we function and affects our propensity to get diseases such as obesity and diabetes. A major goal of Biomedical Research is to uncover which nutrients and metabolites affect our physiology on the one hand and, which of our genes mediate the physiological response to these molecules on the other. We have recently developed an innovative interspecies systems biology model of the nematode C. elegans and its bacterial diet to address these questions. We have used this model to uncover bacterially derived micronutrients and metabolites that affect gene expression, development and fertility in the worm, and to identify a C. elegans metabolic regulatory network that mediates the response to bacterial nutrients. The effects of different bacteria (and their molecules) are mediated via the animal's intestine, which functions as both a digestive and endocrine system. In the next project we will more precisely define the genes that are affected by different bacterial diets, as well as by vitamin B12 and propionic acid - molecules that are central mediators of the effects we observed. In addition, we will use systems-level phenotypic assays and genetic interaction screens to link diet-induced gene expression changes to physiological outputs such as altered developmental rate, fertility, and lifespan and the ability t response to propionic acid toxicity. Finally, we will dissect the precise mechanisms by which metabolic networks communicate with gene regulatory networks and vice versa using a set of transcription factors that are involved in mediating the response to nutritional cues.

Public Health Relevance

We obtain nutrients not only from our diet, but also from the bacteria that inhabit our gut, which are known as the microbiota. Such nutrients include metabolites like the short chain fatty acid propionic acid as well as the micronutrient vitamin B12, both of which are central to our studies. While there is no doubt that nutrients contribute to our physiology and our propensity to get sick, little is known about which nutrients affect which physiological trait, and the mechanisms by which nutritional input is translated into a physiological output. We will continue to use the interspecies systems biology paradigm that we developed to precisely dissect the mechanisms by which propionic acid and vitamin B12 interact and contribute to a variety of physiological traits and diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK068429-10
Application #
8814454
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Karp, Robert W
Project Start
2004-07-01
Project End
2018-08-31
Budget Start
2014-09-25
Budget End
2015-08-31
Support Year
10
Fiscal Year
2014
Total Cost
$638,661
Indirect Cost
$257,371
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Watson, Emma; Walhout, Albertha J M (2014) Caenorhabditis elegans metabolic gene regulatory networks govern the cellular economy. Trends Endocrinol Metab 25:502-8
Watson, Emma; MacNeil, Lesley T; Ritter, Ashlyn D et al. (2014) Interspecies systems biology uncovers metabolites affecting C. elegans gene expression and life history traits. Cell 156:759-70
Walhout, Albertha J M (2014) Genetic adaptation to diet preserves longevity. Cell Metab 19:177-8
Fuxman Bass, Juan I; Tamburino, Alex M; Mori, Akihiro et al. (2014) Transcription factor binding to Caenorhabditis elegans first introns reveals lack of redundancy with gene promoters. Nucleic Acids Res 42:153-62
Watson, Emma; MacNeil, Lesley T; Arda, H Efsun et al. (2013) Integration of metabolic and gene regulatory networks modulates the C. elegans dietary response. Cell 153:253-66
MacNeil, Lesley T; Watson, Emma; Arda, H Efsun et al. (2013) Diet-induced developmental acceleration independent of TOR and insulin in C. elegans. Cell 153:240-52
Reece-Hoyes, John S; Pons, Carles; Diallo, Alos et al. (2013) Extensive rewiring and complex evolutionary dynamics in a C. elegans multiparameter transcription factor network. Mol Cell 51:116-27
Reece-Hoyes, John S; Walhout, Albertha J M (2012) Gene-centered yeast one-hybrid assays. Methods Mol Biol 812:189-208
Feng, Huiyun; Reece-Hoyes, John S; Walhout, Albertha J M et al. (2012) A regulatory cascade of three transcription factors in a single specific neuron, DVC, in Caenorhabditis elegans. Gene 494:73-84
Reece-Hoyes, John S; Barutcu, A Rasim; McCord, Rachel Patton et al. (2011) Yeast one-hybrid assays for gene-centered human gene regulatory network mapping. Nat Methods 8:1050-2

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