GSBS Dissertations and Theses

Approval Date

9-17-2015

Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program

Department

Program in Molecular Medicine

First Thesis Advisor

Marian Walhout, PhD

Keywords

Caenorhabditis elegans, Diet, Caenorhabditis elegans, Metabolism, Vitamin B 12 Deficiency, Gene Regulatory Networks, Homeostasis

Subjects

Dissertations, UMMS; Caenorhabditis elegans; Diet; Caenorhabditis elegans; Metabolism; Vitamin B 12 Deficiency; Gene Regulatory Networks; Homeostasis

Abstract

Maintaining cellular homeostasis is a complex task, which involves monitoring energy states and essential nutrients, regulating metabolic fluxes to accommodate energy and biomass needs, and preventing buildup of potentially toxic metabolic intermediates and byproducts. Measures aimed at maintaining a healthy cellular economy inherently depend on the composition of nutrients available to the organism through its diet. We sought to delineate links between dietary composition, metabolic gene regulation, and physiological responses in the model organism C. elegans.

As a soil-dwelling bacterivore, C. elegans encounters diverse bacterial diets. Compared to a diet of E. coli OP50, a diet of Comamonas aquatica accelerates C. elegans developmental rate, alters egg-laying dynamics and shortens lifespan. These physiological responses are accompanied by gene expression changes. Taking advantage of this natural, genetically tractable predator-prey system, we performed genetic screens i) in C. elegans to identify regulators of diet-responsive genes, and ii) in E. coli and Comamonas to determine dietary factors driving transcriptional responses in C. elegans. We identified a C. elegans transcriptional program that regulates metabolic genes in response to vitamin B12 content in the bacterial diet. Interestingly, several B12- repressed metabolic genes of unknown function are highly activated when B12- dependent propionyl-CoA breakdown is impaired, and inactivation of these genes renders animals sensitive to propionate-induced toxicity. We provide genetic and metabolomic evidence in support of the hypothesis that these genes form a parallel, B12-independent, β-oxidation-like propionate breakdown shunt in C. elegans, similar to the pathway utilized by organisms like yeast and plants that do not use vitamin B12.

DOI

10.13028/M2TS3N

Rights and Permissions

Copyright is held by the author, with all rights reserved.

 
 

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