A Systems-Level Study of Transcriptional Regulation of C. elegans Metabolism

Abstract

Metabolism is controlled to ensure organismal development and homeostasis. Several mechanisms regulate metabolism, including allosteric control and transcriptional regulation of metabolic enzymes and transporters. Until now, metabolism regulation has mostly been described for individual genes and pathways, and the extent of transcriptional regulation of the entire metabolic network largely remains largely unknown. In the first part of this thesis, I used variation in mRNA levels as a proxy for transcriptional regulation of metabolism and found that three-quarters of all metabolic genes are transcriptionally regulated in the nematode Caenorhabditis elegans. I also found that many annotated metabolic pathways are coexpressed. With the aid of gene expression data and the iCEL1314 metabolic network model, I defined coregulated sub-pathways in an unbiased manner. By utilizing a large gene expression compendium, I determined the conditions under which sub-pathways exhibit strong coexpression. Additionally, we developed 'WormClust', a web application that facilitates a gene-by-gene query of genes to view their association with metabolic (sub)- pathways. In the second part of this thesis, I addressed the "missing" annotations in C. elegans metabolism. Through the analysis of various datasets spanning space, time, and conditions, I associated orphan metabolic genes, transporters, transcription factors, and RNA-binding proteins with the existing metabolic network. Overall, this study illuminates the ubiquity of transcriptional regulation of metabolism and provides a blueprint for similar studies in other organisms, including humans.