Abstract SY37-03: Clock-HIF signaling in the epigenetic control of glucose metabolism

Abstract

Abstract Circadian systems play a central role in energy harvesting and storage across daily cycles of fuel availability. In vertebrates, clock genes promote metabolic constancy by coordinating the phase and expression of genes involved in glycolytic and oxidative metabolism. Our previous studies, as well as those from others, revealed that circadian transcription factors (TFs) display functional interactions with the hypoxia-inducible factor (HIF) pathway. Our previous studies demonstrated impaired hypoxic expression of known canonical HIF target genes in Bmal1-/- myotubes and fibroblasts, including those involved in anaerobic glycolysis, angiogenesis, and the HIF pathway. We also observed time-of-day-dependent activation of HIF targets in muscle tissue, raising the possibility that the clock acts to ‘gate’ the induction of HIF targets at different circadian phases. Moreover, we found that hypoxia and HIF can reciprocally regulate direct BMAL1 targets, suggesting a close association between hypoxic and circadian transcriptional networks. Finally, transcriptome profiling studies reveal strikingly little overlap in the subset of BMAL1-dependent genes in normoxia versus hypoxia, suggesting either global remodeling of ‘accessible’ chromatin at sites of promoters and enhancers allowing for altered BMAL1-dependent transcription. Collectively, our data reveal coupling of the HIF and circadian TF pathways producing rhythmic adaptation to hypoxic stress. Citation Format: Clara Bien Peek. Clock-HIF signaling in the epigenetic control of glucose metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY37-03.