Genetic approaches to understand cellular responses to oxygen availability

Oxygen-sensing mechanisms have evolved to allow organisms to respond and adapt to oxygen availability. In metazoans, oxygen-sensing is predominantly mediated by the hypoxia inducible factors (HIFs). These transcription factors are stabilised when oxygen is limiting, activating genes involved in angiogenesis, cell growth, pH regulation and metabolism to reset cell function and adapt to the cellular environment. However, the recognition that other cellular pathways and enzymes can also respond to changes in oxygen abundance provides further complexity. Dissecting this interplay of oxygen-sensing mechanisms has been a key research goal. Here, we review how genetic approaches have contributed to our knowledge of oxygen-sensing pathways which to date have been predominantly focused on the HIF pathway. We discuss how genetic studies have advanced the field and outline the implications and limitations of such approaches for the development of therapies targeting oxygen-sensing mechanisms in human disease.