title: miR-190 Enhances HIF-Dependent Responses to Hypoxia in Drosophila by Inhibiting the Prolyl-4-hydroxylase Fatiga.
abstract: 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.
authors.affiliation: Instituto Leloir, Buenos Aires, Argentina.
authors.forename: Ana Laura
authors.initials: AL
authors.lastname: De Lella Ezcurra
authors.affiliation: Instituto Leloir, Buenos Aires, Argentina.
authors.forename: Agustina Paola
authors.initials: AP
authors.lastname: Bertolin
authors.affiliation: Department of Genetics, Harvard Medical School; Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kim
authors.affiliation: Instituto Leloir, Buenos Aires, Argentina.
authors.forename: Maximiliano Javier
authors.identifier: 0000-0001-9251-1833
authors.initials: MJ
authors.lastname: Katz
authors.affiliation: Instituto Leloir, Buenos Aires, Argentina.
authors.forename: Lautaro
authors.initials: L
authors.lastname: Gándara
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
authors.forename: Tvisha
authors.identifier: 0000-0002-7432-3131
authors.initials: T
authors.lastname: Misra
authors.affiliation: Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.|Institute of Neurobiology, University of Münster; Cluster of Excellence EXC 1003, Cells in Motion, CiM, Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Luschnig
authors.affiliation: Department of Genetics, Harvard Medical School; Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
authors.affiliation: Instituto Leloir, Buenos Aires, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Melani
authors.affiliation: Instituto Leloir, Buenos Aires, Argentina.|Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Pablo
authors.initials: P
authors.lastname: Wappner
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D010100:Oxygen / Q000378:metabolism; D064828:Prolyl Hydroxylases / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D064828:Prolyl Hydroxylases; D010100:Oxygen