Transcriptional Responses to Hypoxia – Beyond HIF

The hypoxia-inducible factor (HIF) pathway has long been considered the primary transcriptional response to oxygen limitation. However, cellular adaptation to hypoxia involves multiple additional oxygen-sensing mechanisms, leading to graded, context-dependent regulation. Oxygen-sensitive 2-oxoglutarate dioxygenases directly regulate chromatin accessibility and DNA methylation, creating epigenetic landscapes that influence gene expression independently of HIF. Alternative transcriptional pathways control essential processes such as sterol biosynthesis and protein folding through the unfolded protein response (reviewed in detail in the Perspective by Worth and Hammond). Rather than operating in opposition to the HIF pathway, these mechanisms frequently integrate with HIF responses, creating layered regulatory networks that fine-tune cellular adaptation. This integration allows precise tuning of transcriptional output based upon oxygen availability, metabolic state and cellular context. This review provides a comprehensive overview of these multilayered oxygen sensing mechanisms affecting gene expression and examines how they integrate with canonical HIF signalling.