Direct interaction between miR-210-5p and HIF-1α regulates HIF-dependent transcription
Egea, V.; Xavier, B.; Mourao, A.; Ferraro, B.; Matta, L.; Jodeleit, H.; von Hundelshausen, P.; Caca, J.; Sattler, M.; Bartelt, A.; Ries, C.; Weber, C.
Show abstract
Hypoxia-inducible factors (HIFs) coordinate cellular adaptation to oxygen deprivation, yet whether hypoxia-induced microRNAs directly regulate HIF-dependent transcription remains unknown. Here, we identify miR-210-5p as a nuclear hypoxamiR that directly binds HIF-1 and enhances HIF-dependent transcription. Hypoxia induced rapid, HIF-dependent nuclear accumulation of mature miR-210-5p across multiple cell types. Biophysical analyses demonstrated direct interaction between miR-210-5p and the HIF-1 bHLH-PAS domain, while mutational studies identified a conserved 5'motif required for HIF-1 binding but dispensable for repression of the canonical cytoplasmic target ISCU. Functionally, transcriptional activity closely correlated with HIF-1-binding affinity, as binding-deficient variants failed to activate HIF reporters or endogenous target genes. Although AGO2 contributed to hypoxic transcriptional responses, miR-210-5p interacted directly with HIF-1 independently of AGO2. In ischemic myocardium, nuclear enrichment of miR-210-5p and its proximity to HIF-1 support the physiological relevance of this mechanism, revealing a previously unrecognized RNA-mediated layer of HIF transcriptional regulation.
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