C. Elegans Metabolic Gene Regulatory Networks: A Dissertation

Abstract

In multicellular organisms, determining when and where genes will be expressed is critical for their development and physiology. Transcription factors (TFs) are major specifiers of differential gene expression. By establishing physical contacts with the regulatory elements of their target genes, TFs often determine whether the target genes will be expressed or not. These physical and/or regulatory TF-DNA interactions can be modeled into gene regulatory networks (GRNs), which provide a systems-level view of differential gene expression. Thus far, much of the GRN delineation efforts focused on metazoan development, whereas the organization of GRNs that pertain to systems physiology remains mostly unexplored. My work has focused on delineating the first gene regulatory network of the nematode Caenorhabditis elegans metabolic genes, and investigating how this network relates to the energy homeostasis of the nematode. The resulting metabolic GRN consists of ~70 metabolic genes, 100 TFs and more than 500 protein–DNA interactions. It also includes novel protein-protein interactions involving the metabolic transcriptional cofactor MDT-15 and several TFs that occur in the metabolic GRN. On a global level, we found that the metabolic GRN is enriched for nuclear hormone receptors (NHRs). NHRs form a special class of TFs that can interact with diffusible biomolecules and are well-known regulators of lipid metabolism in other organisms, including humans. Interestingly, NHRs comprise the largest family of TFs in nematodes; the C. elegans genome encodes 284 NHRs, most of which are uncharacterized. In our study, we show that the C. elegans NHRs that we retrieved in the metabolic GRN organize into network modules, and that most of these NHRs function to maintain lipid homeostasis in the nematode. Network modularity has been proposed to facilitate rapid and robust changes in gene expression. Our results suggest that the C. elegans metabolic GRN may have evolved by combining NHR family expansion with the specific modular wiring of NHRs to enable the rapid adaptation of the animal to different environmental cues.