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miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga.

  • De Lella Ezcurra AL Instituto Leloir, Buenos Aires, Argentina.
  • Bertolin AP Instituto Leloir, Buenos Aires, Argentina.
  • Kim K Department of Genetics, Harvard Medical School; Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
  • Katz MJ Instituto Leloir, Buenos Aires, Argentina.
  • Gándara L Instituto Leloir, Buenos Aires, Argentina.
  • Misra T Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
  • Luschnig S Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
  • Perrimon N Department of Genetics, Harvard Medical School; Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
  • Melani M Instituto Leloir, Buenos Aires, Argentina.
  • Wappner P Instituto Leloir, Buenos Aires, Argentina.
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  • 2016-05-26
Published in:
  • PLoS genetics. - 2016
Animals
Cell Hypoxia
Drosophila melanogaster
Gene Expression Regulation
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
MicroRNAs
Oxygen
Prolyl Hydroxylases
Transcription, Genetic
English Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFα is hydroxylated by specific prolyl-4-hydroxylases, targeting it for proteasomal degradation, while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability, leading to HIFα accumulation and expression of HIF target genes. To identify microRNAs required for maximal HIF activity, we conducted an overexpression screen in Drosophila melanogaster, evaluating the induction of a HIF transcriptional reporter. miR-190 overexpression enhanced HIF-dependent biological responses, including terminal sprouting of the tracheal system, while in miR-190 loss of function embryos the hypoxic response was impaired. In hypoxic conditions, miR-190 expression was upregulated and required for induction of HIF target genes by directly inhibiting the HIF prolyl-4-hydroxylase Fatiga. Thus, miR-190 is a novel regulator of the hypoxia response that represses the oxygen sensor Fatiga, leading to HIFα stabilization and enhancement of hypoxic responses.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/263486
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