RNA modification in cardiometabolic disease

PROJECT SUMMARY Perturbations in metabolic pathways form the epicenter of some of the most devasting threats to mankind, including cardiovascular disease, obesity and NASH. Proper maintenance of metabolic homeostasis requires precise and synchronized control of gene regulation. Recently, the discovery that thousands of mammalian RNAs undergo chemical modifications that powerfully impacts transcript dynamics expands our understanding of gene regulatory mechanisms. N6-methyladenosine methylation (m6A) is the most common internal RNA modification. Multiple lines of evidence suggest that m6A plays a critical role in organismal biology, including stem cell renewal, however, the impact of chemical modifications on RNA in metabolic control is less well understood. The objective of this proposal is to define the physiologic contribution and mechanisms of RNA modifications in metabolism. Capitalizing on our preliminary studies showing that the hepatic m6A landscape is altered in response to diet and strongly enriches lipogenic RNAs, we hypothesize that dynamic RNA modifications are essential for tight regulation of hepatic lipid metabolism. Reinforcing this premise, our studies show that liver-specific knockout of m6A installing machinery leads to increased lipogenesis and alterations in hepatic lipid composition. In aim1, we investigate the function of m6A in hepatic lipid metabolism and fatty liver disease as well as explore opportunities for RNA modification based therapeutic strategies in metabolic disease. In aim2, we define how m6A modifications impact lipogenesis and decipher the hierarchical and cooperative relationship between m6A modifying enzymes and canonical metabolic transcriptional modulators. Our proposed studies are expected to shed fundamental insight into novel mechanisms involved in metabolic control and a model by which RNA modifications can impact health and disease states. In summary, our studies identify a new pathway for lipid degradation and in this application, we propose a series of molecular, cell biological, and animal studies to extend our preliminary observations and test out hypothesis.