HIF-2α regulates Oct-4:: effects of hypoxia on stem cell function, embryonic development, and tumor growth

The division, differentiation, and function of stem cells and multipotent progenitors are influenced by complex signals in the microenvironment, including oxygen availability. Using a genetic "knock-in" strategy, we demonstrate that targeted replacement of the oxygen-regulated transcription factor HIF-1 alpha with HIF-2 alpha results in expanded expression of HIF-2 alpha-specific target genes including Oct-4, a transcription factor essential for maintaining stem cell pluripotency. We show that HIF-2 alpha, but not HIF-1 alpha, binds to the Oct-4 promoter and induces Oct-4 expression and transcriptional activity, thereby contributing to impaired development in homozygous Hif-2 alpha KI/KI embryos, defective hematopoietic stem cell differentiation in embryoid bodies, and large embryonic stem cell (ES)-derived tumors characterized by altered cellular differentiation. Furthermore, loss of HIF-2 alpha severely reduces the number of embryonic primordial germ cells, which require Oct-4 expression for survival and/or maintenance. These results identify Oct-4 as a HIF-2 alpha-specific target gene and indicate that HIF-2 alpha can regulate stem cell function and/or differentiation through activation of Oct-4, which in turn contributes to HIF-2 alpha's tumor promoting activity.