Obesity is the fastest growing health problem in the US and is associated with an increased risk of type 2 diabetes, heart disease and certain forms of cancer. Obesity is, in part, a genetic disorder and several genes that are involved in the disease have been identified. However, these likely constitute only the """"""""tip of the iceberg"""""""" because more potential fat genes are being identified in model organisms. For example, approximately 400 novel genes involved in fat metabolism (hereafter referred to as """"""""fat genes"""""""") have recently been identified in the nematode Caenorhabditis elegans. One of the main questions is how these genes function together in fat metabolism and whether any of these genes may be suitable therapeutic targets for the treatment or prevention of obesity. In both humans and nematodes, several fat genes encode regulatory transcription factors (""""""""fat TFs""""""""). We hypothesize that some of these TFs regulate the expression of many fat genes and that their human homologs may be excellent therapeutic targets because the modulation of these TFs affects many aspects of fat biology. We, and others, have shown that proteins function in the context of intricate molecular networks. Here, we propose to identify and study the physical and functional interactions between fat genes and the TFs that regulate their expression using high-throughput, functional genomic approaches in the experimentally tractable model organism C. elegans. By modeling these interactions into transcription regulatory networks we may be able to identify one, or a few, TFs that appear as """"""""network hubs"""""""" and that may, therefore, play a central role in fat gene expression. Our long-term goal is to understand fat gene expression at a systems level by comprehensively mapping and studying worm fat gene networks. Here, we will test the feasibility of this using a set of 32 """"""""core fat genes"""""""", before embarking on a larger scale project. We have chosen this set of genes because they appear to play a central role in fat metabolism. In my lab, we have all the necessary tools and methods to undertake this exciting project, including a collection of cloned worm open reading frames and a collection of cloned worm gene promoters. In addition, we recently developed a version of the yeast one-hybrid system that enables us to map fat TF-fat gene interactions in a high-throughput manner.
