HIF- and non-HIF-Regulated Hypoxic Responses Require the Estrogen-Related Receptor in Drosophila. Keith D. Baker¹, Yan Li¹, Divya Padmanabha¹, Luciana B. Gentile¹, Catherine I. Dumur², Robert B. Beckstead³. 1) Biochemistry and Molecular Biology, VCU School of Medicine, Richmond, VA; 2) Pathology, VCU School of Medicine, Richmond, VA; 3) Poultry Science, University of Georgia, Athens, GA.

   Low-oxygen tolerance is supported by an adaptive response that includes a coordinate shift in metabolism and the activation of a transcriptional program that is driven by the hypoxia-inducible factor (HIF) pathway. The precise contribution of HIF-1 in the adaptive response, however, has not been determined. Here, we investigate how HIF influences hypoxic adaptation throughout Drosophila development. We find that hypoxic-induced transcriptional changes are comprised of HIF-dependent and HIF-independent pathways that are distinct and separable. We show that normoxic set-points of carbohydrate metabolites are significantly altered in sima mutants and that these animals are unable to mobilize glycogen in hypoxia. Furthermore, we find that the estrogen-related receptor (dERR), which is a global regulator of aerobic glycolysis in larvae, is required for a competent hypoxic response. dERR binds to dHIF and participates in the HIF-dependent transcriptional program in hypoxia. In addition, dERR acts in the absence of dHIF in hypoxia and a significant portion of HIF-independent transcriptional responses can be attributed to dERR actions, including upregulation of glycolytic transcripts. These results indicate that competent hypoxic responses arise from complex interactions between HIF-dependent and -independent mechanisms, and that dERR plays a central role in both of these programs.