HIF- and Non-HIF-Regulated Hypoxic Responses Require the Estrogen-Related Receptor in Drosophila melanogaster

• Published in: PLoS genetics Vol. 9; no. 1; p. e1003230
• Main Authors: Li, Yan, Padmanabha, Divya, Gentile, Luciana B., Dumur, Catherine I., Beckstead, Robert B., Baker, Keith D.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2013; Public Library of Science (PLoS)
• Subjects: Animals; Biology; DNA-Binding Proteins - genetics; Drosophila; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Estrogen; Estrogens; Estrogens - genetics; Gene Expression Regulation - physiology; Genes; Genetic aspects; Genetic transcription; Glycolysis; Health aspects; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Hypoxia-Inducible Factor 1 - genetics; Hypoxia-Inducible Factor 1 - metabolism; Metabolites; Oxygen; Physiological aspects; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Transcriptional Activation; United States
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003230

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-1a in the adaptive response, however, has not been determined. Here, we investigate how HIF influences hypoxic adaptation throughout Drosophila melanogaster 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 dHIFa and participates in the HIF-dependent transcriptional program in hypoxia. In addition, dERR acts in the absence of dHIFa 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.