Acute hypoxia suppresses blood glycolysis in saker falcons (Falco cherrug) via NR3C1-mediated repression of HK1: evidence from hematological and epigenomic profiling

Climate change is driving high-altitude birds to move to even higher elevations, but their responses to these new environments remain poorly understood. In this study, we investigated physiological and molecular responses of saker falcons (Falco cherrug) inhabiting the Qinghai-Xizang Plateau when exposed to simulated altitudes of 5000-6000 m, where hypoxic conditions are more severe than their natural habitats (approximately 4300 m). Although GPS tracking data showed that juvenile saker falcons maintained consistent activity levels between 4000-5000 m and 5000-6000 m, pre-fledging sakers exhibited significant increases in hemoglobin concentration and blood glucose levels after a three-day treatment in hypoxia chambers simulating an altitude of 6000 m. Transcriptome analysis revealed a downregulation of glycolysis in these hypoxia-treated individuals, including a significant decrease in the expression of hexokinase-1 (HK1), a key enzymatic gene in the glycolytic pathway. ATAC-seq analysis further identified a highly accessible region within the HK1 gene that contains two cis-regulatory elements for the transcription factor NR3C1 in the hypoxia-treated group, and the expression of NR3C1 was negatively correlated with HK1. Notably, these cis-regulatory elements were both unique and highly conserved in birds, suggesting their potential role in the response of highland birds to hypoxic stress. These findings enhance our understanding of avian responses to acute hypoxia and offer valuable insights into the conservation of bird species on the Qinghai-Xizang Plateau and other high-altitude regions, especially in the face of rapid global climate change.