EPAS1 resistance to miRNA-based regulation contributes to prolonged expression of HIF-2 during hypoxia in human endothelial cells.

The cellular adaptation to hypoxia is regulated by hypoxia inducible factors: HIF-1 and HIF-2. HIF-1 mediates response to acute hypoxia, whereas HIF-2 allows adaptation to chronic oxygen deprivation. The hypoxic transition from HIF-1 to HIF-2 is possible due to the low stability of HIF-1α subunit transcript (HIF1A) and the stable mRNA of HIF-2α (EPAS1). Notably, although many micro-RNAs (miRNAs) that regulate endothelial HIF-1 levels during hypoxia have been identified, in case of HIF-2, no analogous ones have been found so far. In this work, using different methods, we tested 23 microRNA that were predicted to interact with the EPAS1 transcript (18 of which were induced during prolonged hypoxia), and we demonstrated that none of them were functional in vitro. This suggests that HIF-2α transcript is much less prone to miRNA-related destabilization during hypoxia.