HIF- and non-HIF-regulated hypoxic responses require the estrogen-related receptor in Drosophila melanogaster

PLoS Genet. 2013;9(1):e1003230. doi: 10.1371/journal.pgen.1003230. Epub 2013 Jan 31.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • Drosophila Proteins* / genetics
  • Drosophila Proteins* / metabolism
  • Drosophila melanogaster* / genetics
  • Estrogens / genetics
  • Gene Expression Regulation / physiology
  • Glycolysis
  • Hypoxia* / genetics
  • Hypoxia* / metabolism
  • Hypoxia-Inducible Factor 1* / genetics
  • Hypoxia-Inducible Factor 1* / metabolism
  • Oxygen
  • Receptors, Estrogen* / genetics
  • Receptors, Estrogen* / metabolism
  • Transcriptional Activation

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • ERR protein, Drosophila
  • Estrogens
  • Hypoxia-Inducible Factor 1
  • Receptors, Estrogen
  • Oxygen