Regulation of Liver Metabolism by lncRNAs

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Project Summary The current research proposal is to investigate the physiological function of Gm11967, a novel insulin-dependent long non-coding RNA (lncRNA) identified during my current K01 award. Despite ncRNAs accounting for a majority of the transcriptome, very little is known about their biological significance and functional targets. lncRNAs are a large and diverse class of RNA transcripts with a length of more than 200 nucleotides that do not encode proteins. To date, very few lncRNAs have been characterized in detail; however, recent work has suggested a potential role for lncRNA in metabolic disorders such as diabetes and obesity. Therefore, we re- analyzed genome-wide data sets generated during my K01 award to interrogate the role of hepatic insulin signaling on lncRNA expression to identify novel, metabolically regulated lncRNAs. We identified Gm11967 as one of the most significantly induced lncRNA in liver in vivo. Using mouse genetics, we demonstrated Gm11967 is downstream of the Akt-Foxo1 axis, a central signaling node involved in hepatic glucose and lipid metabolism. Gm11967 shares a transcription start site with glucokinase, a potent insulin-regulated gene that is the focus of my current K01. Given its robust activation with feeding, dependency on insulin action, and close association with glucokinase expression, we hypothesized that Gm11967 plays a central role in the regulation of hepatic glucose and lipid metabolism. We will perform gain and loss of function experiments in vivo to elucidate the biological function of Gm11967 in hepatocytes. In addition, we will perform chromatin isolation by RNA purification (ChIRP) followed by mass spectrometry and/or deep sequencing to identify functional proteomic and genomic targets of Gm11967. Based on my training and expertise obtained during the course of my K01, I have the independence and technical skillsets necessary to complete this proposal. Importantly, these data will build upon the strong foundation of my K01 and will enable new lines of investigation that will lead to a future R01 application.