Duan C. Hypoxia-inducible factor 3 biology: complexities and emerging themes. Am J Physiol Cell Physiol 310: C260 -C269, 2016. doi:10.1152/ajpcell.00315.2015.-The hypoxia-inducible factor (HIF) family has three distinct members in most vertebrates. All three HIFs consist of a unique and oxygen-labile ␣-subunit and a common and stable -subunit. While HIF-1 and HIF-2 function as master regulators of the transcriptional response to hypoxia, much less is known about HIF-3. The HIF-3␣ gene gives rise to multiple HIF-3␣ variants due to the utilization of different promoters, different transcription initiation sites, and alternative splicing. These HIF-3␣ variants are expressed in different tissues, at different developmental stages, and are differentially regulated by hypoxia and other factors. Recent studies suggest that different HIF-3␣ variants have different and even opposite functions. There is strong evidence that full-length HIF-3␣ protein functions as an oxygen-regulated transcription activator and that it activates a unique transcriptional program in response to hypoxia. Many HIF-3␣ target genes have been identified. While some short HIF-3␣ variants act as dominant-negative regulators of HIF-1/2␣ actions, other HIF-3␣ variants can inhibit HIF-1/2␣ actions by competing for the common HIF-. There are also a number of HIF-3␣ variants yet to be explored. Future studies of these naturally occurring HIF-3␣ variants will provide new and important insights into HIF biology and may lead to the development of new therapeutic strategies.hypoxia-inducible factor; alternative splicing; oxygen-dependent degradation; gene expression OXYGEN IS AN ESSENTIAL MOLECULE required for cellular respiration and efficient energy production. Hypoxia, a condition in which an organism or a cell is deprived of adequate oxygen (e.g., when oxygen demand exceeds oxygen supply), occurs in developing embryos and adult tissues and plays key roles in stem cell biology, development, and adult physiology. Hypoxia is also frequently associated with pathological states such as ischemia, arthritis, inflammation, and tumorigenesis. Hypoxia triggers complex adaptive responses and activates the expression of numerous genes. These hypoxia-responsive genes are involved in changes in erythropoiesis, angiogenesis, metabolic reprograming, cell-cycle regulation, and tumorigenesis (9,39,(43)(44)(45). The transcriptional response to hypoxia is coordinated by hypoxiainducible factors (HIFs). HIFs are heterodimers, consisting of an oxygen-labile HIF␣ subunit and a stable HIF- subunit [also known as aryl hydrocarbon receptor nuclear translocator (ARNT)]. In human and other vertebrate species, there are three distinct HIF␣ genes. Much of our knowledge about HIF signaling is derived from studies on HIF-1␣ and HIF-2␣ (9, 39, 43-45). Both HIF-1␣ and HIF-2␣ contain a basic helix-loophelix (bHLH) domain, two Per-Arnt-Sim (PAS) domains, a PAS-associated COOH-terminal (PAC) domain; an oxygendependent degradation (ODD) domain; an NH 2 -terminal transactivation domain (N...