By the year 2030, the World Health Organization projects the number of people in China with type 2 diabetes (T2D) to reach 42 million. T2D is a multifaceted disease caused by both genetic and environmental factors, and intriguingly, this disease progresses with age. Systems biology approaches have enabled integration of various datasets to enhance the probably of identifying specific biological functions and genes that are causal for a particular disease. Research in the Han lab has recently used a probabilistic network approach to identify regulatory networks and predict causal genes for T2D. Interestingly, many of these genes are key regulators of metabolic pathways rather than genes involved in the metabolic pathway itself. Although many of these regulators, particularly transcription factors, have previously been implicated in T2D development, the mechanisms for how modulating the function of these regulators results in disease remain unclear. In addition, epigenetic regulation is central to transcription factor activity and understanding its role in T2D and aging is still in the early stages..Genome-wide analysis of transcription factor binding and histone modifications, which mediate DNA compaction and cofactor recruitment, has revealed new insights into the regulation of gene expression. How the global pattern of transcription factor binding and chromatin environment is changed during the development of complex phenotypes such as T2D and aging, however, remains unknown..To address the role of key transcription factors and epigenetic modifications in T2D and aging, the following studies are proposed: Aim 1, Characterize changes in transcription factor binding in a high-fat diet model of T2D using chromatin immunoprecipitation combined with deep sequencing (ChIP-seq), computationally determine what other factors may influence binding, and verify these findings through transgenic mouse study. Aim 2, Identify epigenetic changes in histone methylation status involved in T2D and the aging process. These studies combine systems biology approaches with genome-wide transcription factor binding analysis and models of T2D and aging to examine how candidate transcription factors and epigenetic modifications change in these complex phenotypes..Genome-wide transcription factor binding and histone modifications have been shown to be altered by a single extracellular stimulus. Thus, under complex phenotypes such as T2D and aging in which many different signals are simultaneously changing, these global patterns are expected to change, which to date have not been addressed. The results from these studies will provide insight into which key pathways are directly altered by the targeted transcription factors and modifications during the development of these phenotypes, aiding in the identification of mechanisms that specifically target the desired pathway and treat the disease.