The Class I histone deacetylase HDAC3 is an important epigenomic mediator of lipogenesis, circadian signaling, and metabolism in liver, that is a potentially useful therapeutic target to combat metabolic disorders such as Type 2 Diabetes. We have recently discovered that HDAC3 possesses deacetylase- independent functions in hepatic lipid metabolism. I hypothesize that discrete from its enzymatic activity, HDAC3 functions in conjunction with as yet to be discovered protein complexes as a molecular platform to control lipid homeostasis in the liver. My first specific aim is to investigate deacetylase- independent genome-wide transcriptional regulation by HDAC3 in vivo. Comparison of intersecting and divergent transcriptional profiles, genome-wide HDAC3 binding, and histone modifications will be studied to understand the roles of HDAC3 in hepatic lipid regulation. My second specific aim will be to characterize novel HDAC3-containing protein complexes in vivo using state-of-the-art proteomic tools and analyses. New complexes will be investigated using binding-deficient mutants and gain and loss-of function studies for their role in supervising liver transcriptional networks involved in lipogenesis. The results of this study wil elucidate basic mechanisms of transcriptional control of mammalian bioenergetics in the liver. Furthermore, this work may uncover novel mechanisms of metabolic regulation that can be exploited for the development of therapies for the prevention and treatment of metabolic disorders.
The liver is central to organismal control of energy utilization and storage. With metabolic disorders such as Type 2 Diabetes rapidly increasing in prevalence, understanding energy homeostasis in the liver is paramount. The goal of the proposed research is to characterize and differentiate the deacetylase-dependent and -independent functions of HDAC3 in liver metabolism and elucidate the mechanisms of this regulation.