Precise control of hepatic glucose production (HGP) is pivotal to maintain whole-body glucose homeostasis. The evolutionarily conserved transcription factor HNF4? has been extensively studied for its role in hepatic differentiation and function. Hnf4? contains two promoters, P2 and P1, which drive multiple HNF4? isoforms via alternative splicing in a development- and tissue-specific manner. The current dogma is that the P2-derived isoform predominates during fetal development; however, after birth the P1-derived isoform takes over, directing a wide range of liver functions including gluconeogenesis. It is found that the fetal isoform of HNF4? is required for HGP in adult liver. This isoform is acutely induced during fasting and chronically increased in type-2 diabetes (T2D). P2 isoform induction occurs in response to upregulation of TET3, a member of a new class of DNA demethylases not previously shown to be involved in HGP. Furthermore, liver-specific knockdown of either TET3 or the P2 isoform alone improves glucose homeostasis in dietary and genetic mouse models of T2D. It is hypothesized that TET3 is a novel regulator of HGP by epigenetically inducing the HNF4? fetal isoform. To test the hypothesis, the molecular pathways by which TET3 specifically reactivates the P2 promoter will be dissected. The approaches will involve molecular, biochemical, and genome-wide approaches as well as mouse and human primary hepatocytes and mouse models. Upon completion of these studies the mechanisms by which TET3 specifically induces the HNF4? fetal isoform to enhance HGP will be defined. If successful, these studies hold the promise of discovering new therapeutic targets for T2D.
We have discovered that the TET3 dioxygenase promotes gluconeogenesis in adult liver by inducing the HNF4? fetal isoform. We will dissect the molecular mechanism by which TET3 specifically reactivates the fetal promoter of HNF4?. The proposed studies hold the potential of discovering new therapeutic targets for diabetes.
