title: Jumonji Domain Containing Protein 6 Is Decreased in Human Preeclamptic Placentas and Regulates sFLT-1 Splice Variant Production.
abstract: The anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFLT-1), plays a central role in preeclamptic pathophysiology. A splice variant of FLT-1 (VEGF receptor 1), sFLT-1 is released in excessive amounts from the preeclamptic placenta into the maternal circulation, where it causes endothelial dysfunction manifesting as end-organ disease. However, the mechanisms regulating its production within the placenta remain poorly understood. Recently it was shown in endothelial cells that Jumonji domain containing protein 6 (JMJD6) hydroxylates U2 small nuclear ribonucleoprotein auxiliary factor 65-kDa subunit (U2AF65, a component of the splicesome). The hydroxylation by JMJD6 is oxygen dependent. Under hypoxia, JMJD6 is less able to hydroxylate U2AF65, and this unhydroxylated form of U2AF65 biases splicing of FLT-1 to sFLT-1. We assessed whether oxygen-sensing JMJD6 is differentially expressed in preeclamptic placenta and regulates sFLT-1 splicing in placenta via U2AF65. JMJD6 protein expression was significantly reduced in preterm preeclamptic placenta (P < 0.0001; n = 21) relative to preterm controls (n = 10). Exposing both placental and endothelial cells to hypoxia significantly reduced JMJD6 mRNA and increased sFLT-1 mRNA and protein expression. Silencing JMJD6 in primary endothelial and trophoblast cells significantly increased sFLT-1 secretion. Next, we examined whether these molecules may be directly interacting. We demonstrated that placental U2AF65 colocalized with JMJD6. In turn, we found JMJD6 directly interacts with U2AF65, which in turn produces sFLT-1 mRNA transcripts. Taken together, our findings provide evidence that JMJD6 may play a role in regulating the production of sFLT-1 in the preeclamptic placenta. Decreased placental JMJD6 expression may be an important component to the pathophysiology of preeclampsia.
authors.affiliation: Translational Obstetrics Group, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Palmer
authors.affiliation: Translational Obstetrics Group, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
authors.affiliation: Translational Obstetrics Group, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Tuohey
authors.affiliation: Translational Obstetrics Group, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Cannon
authors.affiliation: Translational Obstetrics Group, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Louie
authors.initials: L
authors.lastname: Ye
authors.affiliation: Translational Obstetrics Group, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Hannan
authors.affiliation: Translational Obstetrics Group, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Brownfoot
authors.affiliation: Department of Obstetrics and Gynaecology, Faculty of Medicine, Universidad de los Andes, Santiago, Chile.
authors.forename: Sebastián E
authors.initials: SE
authors.lastname: Illanes
authors.affiliation: Translational Obstetrics Group, University of Melbourne, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Heidelberg, Victoria, Australia t.klino@unimelb.edu.au.
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
mesh_terms: D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D000072668:Splicing Factor U2AF / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D000072668:Splicing Factor U2AF; C000607494:U2AF2 protein, human; C498707:JMJD6 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D010100:Oxygen
keywords: JMJD6; hypoxia; placenta; preeclampsia; pregnancy; sFLT-1