Fatty acid synthase (FAS) is a principal enzyme in the regulation of lipogenesis. The synthesis of fatty acids is an energy expensive process and so the transcription of FAS is tightly regulated by an organism?s nutritional state. FAS transcription is low during fasting and increases drastically in the fed state. The concentration of insulin in circulation parallels that of metabolic fuels and is largely responsible for the increase in FAS transcription upon feeding. USF-1 is a critical component of lipogenic gene transcription and its binding to the FAS promoter region is required for FAS transcription. Several cofactors are recruited to USF1 on the FAS promoter in the presence of elevated insulin, including DNA-PK, P/CAF, BAF60c, and MED17 and thus various signaling pathways converge on USF1 to promote FAS transcription. This study will focus on the characterization of a newly identified USF1 interacting partner and elucidate how this histone demethylase is regulated by fasting/feeding and thus will allow for an improved understanding of the epigenetic regulation of lipogenesis.
Aim 1 of this proposal will focus on the characterization of the interaction between USF1 and this histone demethylase and examine its role in FAS promoter activation.
Aim 2 will assess the in vivo metabolic effects of this histone demethylase in liver by adenovirus-mediated knockdown/overexpression as well as through the utilization of a liver specific knockout.
Aim 3 will focus on the utilization of metabolomic, genomic, and transcriptomic approaches to determine the effect of metabolite flux on demethylase activity and chromatin accessibility, as well as histone demethylase binding and gene expression.
These Aims will thus allow for an improved understanding of the regulation of FAS transcription and lipogenesis, and may reveal novel therapeutic targets for the treatment of obesity, hepatosteatosis, or insulin resistance. The candidate?s plan for career development in the short-term is to gain a mastery of the molecular techniques and approaches used to study epigenetic regulation of transcription, as well as metabolomics and genomics. Long-term plans for career development include improving writing ability by writing more manuscripts and grant applications, and improving communication skills by presenting/discussing work both within the department and at scientific meetings. The candidate?s career goals are to obtain a tenure-track faculty position in a research focused university and to lead an independent laboratory studying metabolic regulation at the molecular and physiological levels. The laboratory of Dr. Hei Sook Sul at UC Berkeley provides an ideal environment for mentored career development as it will allow the candidate to have access to the necessary resources and equipment to complete the proposed work. He will have easy access to co- mentor Dr. Marc Hellerstein within the NST department, as well as co-mentor Dr. Danica Fujimori at the nearby UC San Francisco, and thus will be able to collaborate with both to acquire expertise in metabolomics and epigenetic regulation.
Obesity is a widespread problem that can lead to the development of more harmful disorders such as fatty liver disease, type 2 diabetes, or heart disease. This research will improve our understanding of the mechanisms that control fat production in the liver in response to feeding, and may allow us to identify targets for treatment in order to prevent the accumulation of excess fat.