Zebrafish hif-3α modulates erythropoiesis via regulation of gata-1 to facilitate hypoxia tolerance

The hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) are master regulators of the cellular response to O2. In addition to HIF-1α and HIF-2α, HIF-3α is another identified member of the HIF-α gene family. Even though whether some HIF-3α isoforms have transcriptional activity or repressive activity is still under debate, it is evident that the full length of HIF-3α acts as a transcription factor. However, its function in hypoxia signaling is largely unknown. Here, we showed that loss of hif-3α in zebrafish reduced hypoxia tolerance. Further assays indicated that erythrocyte number was decreased because red blood cell maturation was impeded by hif-3α disruption. We found that gata-1 expression was downregulated in hif-3α-null zebrafish, as were several hematopoietic marker genes, including alas2, band3, hbae1, hbae3 and hbbe1. hif-3α recognized the hypoxia response element (HRE) located in the promoter of gata-1 and directly bound to the promoter to transactivate gata-1 expression. Our results suggested that hif-3α facilities hypoxia tolerance by modulating erythropoiesis via gata-1 regulation.