title: Jumonji Domain Containing Protein 6: A Novel Oxygen Sensor in the Human Placenta.
abstract: Persistent low oxygen is implicated in the pathogenesis of placental-associated pathologies such as preeclampsia, a serious disorder of pregnancy. Emerging evidence implicates a novel family of Jumonji C catalytic domain proteins as mediators of hypoxic gene expression. Here, we investigated the regulatory relationship between Jumonji C domain containing protein 6 (JMJD6) and hypoxia-inducible factor (HIF)1A in the human placenta at physiological and pathological conditions. JMJD6 expression inversely correlated with changes in oxygen tension during early placental development, ie, high at 7-9 weeks when-partial pressure of O2 is low and declining afterwards when-partial pressure of O2 increases. Moreover, JMJD6 protein was significantly elevated in early-onset preeclamptic placentae, localizing to the syncytiotrophoblast layer and syncytial knots. Exposure of primary isolated trophoblast cells, human villous explants, and JEG3 choriocarcinoma cells to low oxygen (3%) and sodium nitroprusside (inducer of oxidative stress) also resulted in elevated JMJD6 levels, which was abrogated by HIF1A knockdown. In normoxia, knockdown of JMJD6 in JEG3 cells stabilized HIF1A with a concomitant decrease in von Hippel-Lindau (VHL) tumor suppressor protein, a negative regulator of HIF1A stability. In contrast, overexpression of JMJD6 enhanced VHL expression and destabilized HIF1A. JMJD6 regulation of VHL stability did not involve the ubiquitin-proteasome system but likely occurred through lysyl hydroxylation and small ubiquitin-like modifier 1-dependent small ubiquitin-like modifierylation. In summary, our data signify a novel role for JMJD6 as an oxygen sensor in the human placenta, and alterations in the JMJD6-VHL-HIF1A feedback loop may indirectly contribute to elevated HIF1A found in preeclampsia.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute (S.A., I.C.), Mount Sinai Hospital, Toronto, M5T 3H7 Ontario, Canada; Department of Obstetrics and Gynecology (I.C.), University of Toronto, Toronto, M5G 1E2 Ontario, Canada; Department of Physiology (S.A., M.P., A.C.), University of Toronto, Toronto, M5S 1A8 Ontario, Canada; Department of Pediatrics (M.P.), University of Toronto, Toronto, M5G 1X8 Ontario, Canada; and The Hospital for Sick Children (M.P.), Toronto, M5G 1X8 Ontario, Canada.
authors.forename: Sruthi
authors.initials: S
authors.lastname: Alahari
authors.affiliation: Lunenfeld-Tanenbaum Research Institute (S.A., I.C.), Mount Sinai Hospital, Toronto, M5T 3H7 Ontario, Canada; Department of Obstetrics and Gynecology (I.C.), University of Toronto, Toronto, M5G 1E2 Ontario, Canada; Department of Physiology (S.A., M.P., A.C.), University of Toronto, Toronto, M5S 1A8 Ontario, Canada; Department of Pediatrics (M.P.), University of Toronto, Toronto, M5G 1X8 Ontario, Canada; and The Hospital for Sick Children (M.P.), Toronto, M5G 1X8 Ontario, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Post
authors.affiliation: Lunenfeld-Tanenbaum Research Institute (S.A., I.C.), Mount Sinai Hospital, Toronto, M5T 3H7 Ontario, Canada; Department of Obstetrics and Gynecology (I.C.), University of Toronto, Toronto, M5G 1E2 Ontario, Canada; Department of Physiology (S.A., M.P., A.C.), University of Toronto, Toronto, M5S 1A8 Ontario, Canada; Department of Pediatrics (M.P.), University of Toronto, Toronto, M5G 1X8 Ontario, Canada; and The Hospital for Sick Children (M.P.), Toronto, M5G 1X8 Ontario, Canada.
authors.forename: Isabella
authors.initials: I
authors.lastname: Caniggia
mesh_terms: D017668:Age of Onset; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D005865:Gestational Age; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010100:Oxygen / Q000378:metabolism* / Q000494:pharmacology; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D010929:Placentation; D011225:Pre-Eclampsia / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy
chemical_list: D015415:Biomarkers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C498707:JMJD6 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; D010100:Oxygen