STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

Abstract

ABSTRACTSTAT3 and HIF1α are two fundamental transcription factors involved in many merging properties, like angiogenesis, metabolism, and cell differentiation. Notably, under pathological conditions, the two factors have been shown to interact genetically, but both the molecular mechanisms underlying such interactions and their relevance under physiological conditions remains unclear. Here we report that STAT3 is required for the HIF1α-dependent response to hypoxia. In Stat3 knock-out pluripotent embryonic stem cells (ESCs), a large fraction of HIF1α target genes is not induced by hypoxia. Mechanistically, STAT3 does not regulate neither HIF1α expression nor stability, rather, it physically interacts with it in the nucleus. In vivo, we observed that both genetic and chemical inactivation of Stat3 blunted physiological responses to hypoxia, such as angiogenesis, erythropoiesis, and immune cell mobilization. Such defects were accompanied with faulty transcriptional activity of HIF1α. In sum, our data reveal that STAT3 and HIF1α cooperatively mediate the physiological response to hypoxia.