Research Article: The Histone Demethylase Jhdm1a Regulates Hepatic Gluconeogenesis

Date Published: June 14, 2012

Publisher: Public Library of Science

Author(s): Dongning Pan, Chunxiao Mao, Tie Zou, Annie Y. Yao, Marcus P. Cooper, Victor Boyartchuk, Yong-Xu Wang, Juleen R. Zierath

Abstract: Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes.

Partial Text: Hepatic glucose production is critical for the maintenance of normal blood levels to meet whole-body fuel requirements. In the early phase of postabsorptive state, circulating glucose is supplied from breakdown of liver glycogen stores. When fasting progresses, gluconeogenesis, which utilizes non-carbohydrate precursors to de novo synthesize glucose, becomes the major form of hepatic glucose production [1], [2]. In both type 1 and type 2 diabetes, gluconeogenesis is exaggerated and contributes to hyperglycemia [3]–[5].

In recent years, a number of histone demethylases have been identified [17]–[20]. While these exciting discoveries dramatically reversed our previous view that histone methylation was a stable, non-erasable marker, our knowledge regarding the functions of these demethylases in biological processes and diseases is very limited. Here, through an shRNA screen against the known histone demethylases, we identify Jhdm1a negatively regulates gluconeogenic gene PEPCK and G6Pase expression both in vitro and in vivo. Phenotypically, silencing of Jhdm1a elevates glucose production, whereas its ectopic expression lowers blood glucose levels in diabetes. Interestingly, our studies suggest that Jhdm1a does not appear to control PEPCK and G6Pase expression directly. Rather, Jhdm1a exerts its function through C/EBPα. The role of C/EBPα in gluconeogenesis has been well established [25]–[29]. We found that Jhdm1a negatively modulates the expression of C/EBPα through active demethylation on the C/EBPα locus. Therefore, our work potentially uncovers a novel molecular mechanism in gluconeogenesis, where histone demethylation regulates a key gluconeogenic transcription factor. However, it is important to note that our in vivo studies were performed using adenoviral infusion to acutely manipulate hepatic Jhdm1a level, therefore, chronic and more physiological and pathophysiological roles of Jhdm1a in gluconeogenesis remain to be addressed in detail with liver-specific Jhdm1a knockout and transgenic models. In addition, as genetic variations at the Jhdm1a locus are present in human population, it will be interesting to analyze whether these variations are associated with type 2 diabetes.