- Hypoxia-response elements (HREs) are short, cis-acting DNA sequences found within the promoter or enhancer regions of various genes that are activated in response to low oxygen conditions (hypoxia).
- They serve as the binding sites for hypoxia-inducible factors (HIFs), a family of transcription factors that orchestrate cellular adaptation to hypoxic stress. The consensus sequence of an HRE is typically represented as 5′-RCGTG-3′ (where R is a purine), often located within larger regulatory regions that also contain accessory motifs enhancing transcriptional efficiency. By enabling the binding of stabilized HIF complexes, HREs initiate the transcription of a wide array of genes involved in angiogenesis, erythropoiesis, glycolysis, and cell survival.
- The core mechanism of HRE function relies on the stabilization of HIF-α subunits under hypoxic conditions. In normoxia, prolyl hydroxylases (PHDs) hydroxylate HIF-α, leading to its recognition by the von Hippel–Lindau (VHL) protein and subsequent degradation. Under hypoxia, hydroxylation is suppressed, allowing HIF-α to accumulate, translocate to the nucleus, and dimerize with HIF-β. This heterodimer specifically recognizes HREs in the DNA and recruits co-activators such as CBP/p300, resulting in transcriptional activation of hypoxia-responsive genes. Through this mechanism, HREs function as molecular switches that translate oxygen availability into gene expression programs.
- Genes regulated by HREs play central roles in maintaining tissue homeostasis under oxygen-limited conditions. For example, vascular endothelial growth factor (VEGF), erythropoietin (EPO), and glucose transporters (GLUT1) are all controlled by HREs, enabling cells to increase oxygen delivery, enhance red blood cell production, and adapt metabolism toward anaerobic glycolysis. In the placenta, HRE-driven regulation supports fetal development in a relatively hypoxic environment, while in tumors, the HIF–HRE axis drives angiogenesis and metabolic reprogramming that facilitate cancer progression.
- The functional significance of HREs extends beyond basic physiology into disease pathogenesis. In cancer, chronic hypoxia stabilizes HIF and induces HRE-mediated expression of genes that promote angiogenesis, invasion, and therapy resistance. In ischemic diseases such as stroke and myocardial infarction, activation of HRE-dependent pathways aids tissue survival and repair. These diverse effects make HREs attractive therapeutic targets. For instance, artificial HREs have been incorporated into gene therapy vectors to achieve hypoxia-specific expression of therapeutic genes, minimizing off-target effects and improving safety. Conversely, disrupting HIF–HRE interactions is a major strategy under investigation for anti-cancer therapies.
