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

Abstract

The hypoxia-inducible factors 1α and 2α (HIF1α and HIF2α) are master regulators of the cellular response to O_2. In addition to HIF1α and HIF2α, HIF3α is another identified member of the HIFα family. Even though the question of whether some HIF3α isoforms have transcriptional activity or repressive activity is still under debate, it is evident that the full length of HIF3α acts as a transcription factor. However, its function in hypoxia signaling is largely unknown. Here, we show that loss of <i>hif3</i><i>a</i> in zebrafish reduced hypoxia tolerance. Further assays indicated that erythrocyte number was decreased because red blood cell maturation was impeded by <i>hif3</i><i>a</i> disruption. We found that <i>gata1</i> expression was downregulated in <i>hif3</i><i>a</i> null zebrafish, as were several hematopoietic marker genes, including <i>alas2</i>, <i>band3</i>, <i>hbae1</i>, <i>hbae3</i> and <i>hbbe1</i> Hif3α recognized the hypoxia response element located in the promoter of <i>gata1</i> and directly bound to the promoter to transactivate <i>gata1</i> expression. Our results suggested that <i>hif3</i><i>a</i> facilities hypoxia tolerance by modulating erythropoiesis via <i>gata1</i> regulation.