Gene Regulation by HIFs during Hypoxia 2022

Dear Colleagues,

The limitation of oxygen delivery in human cells and/or tissues, a condition  termed hypoxia, can occur during healthy activities, such as intense muscular exercise and moving to a high altitude, but is also a characteristic of many pathological conditions such as pulmonary dysfunction, ischemia, inflammation and cancer. As a response to hypoxia, cells mount a remarkable transcriptional response, involving more than a thousand genes, which can allow adaptation and continued survival under low oxygen conditions. The key elements of this response are hypoxia inducible transcription factors (HIFs).

The importance of HIFs for both health and disease has been highlighted by the recent award of the Nobel Prize 2019 in Physiology or Medicine jointly to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza "for their discoveries of how cells sense and adapt to oxygen availability." This event underlined the great progress that had been made the past three decades in the field of oxygen homeostatis and the long path that had been trodden from the discovery of HIF-1 as a transcription factor regulating erythropoietin (Epo) gene expression in liver cells, to the direct or indirect involvement of HIFs to most physiological and pathophysiological conditions. These stem from processes controlling development, differentiation, erythropoiesis, angiogenesis, osteogenesis and immune function at the organismal level, to cell autonomous pathways involving metabolism, apoptosis, cell cycle control, migration and many others. These findings have also been translated to the discovery and clinical application of HIF inducers as drugs for anemia treatment and HIF inhibitors as anticancer agents.

Single gene expression experiments, as well as genome-wide studies, have shown that HIFs can stimulate the expression of hundreds of genes by binding  to a short consensus DNA sequence termed Hypoxia Response Element (HRE) and acting as transcriptional activators. As the genes controlled directly by HIFs not only include effector proteins but also other transcriptional factors, miRNAs and long non-coding RNAs, HIF activation can lead to an even more greater number of up- or down-regulated genes when cells are exposed to hypoxia.  Therefore, the inventory of the genes affected by HIFs and hypoxia is ever-growing. However, it has also been made clear that the repertoire of HIF gene targets is context dependent and significant variation is observed between different cell types or tissues. To increase the complexity, the genes and pathways affected by the two major and most well studied HIF isoforms, HIF-1 and HIF-2, are mostly not overlapping, despite the fact that both HIFs have similar DNA binding motifs. It is also evident that there is extensive, and in many cases poorly characterized, synergy between HIFs and other transcription factors or histone-bound elements, chromatin remodeling agents and co-activators or repressors that affects target gene specificity and the extent of their induction. This co-operation may be controlled by several different signaling or oncogenic pathways and facilitate a still unexplored crosstalk between the hypoxia response and the cellular reaction to other types of stress or extracellular cues and signals. Therefore, there are still important questions remaining about HIF function and its regulation downstream of their oxygen-dependent activation, which is necessary for integrating HIF activity into a particular cellular physiology for optimal tolerance of hypoxia.

Prof. Dr. George Simos
Dr. Ilias Mylonis
Dr. Efrosyni Paraskeva
Guest Editors

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