Compromised JMJD6 Histone Demethylase Activity Affects VHL Gene Repression in Preeclampsia

Abstract

Context The von Hippel Lindau (VHL) protein is a key executor of the cellular hypoxic response that is compromised in preeclampsia, a serious disorder complicating 5% to 7% of pregnancies. To date, the mechanisms controlling VHL gene expression in the human placenta remain elusive. Objective We examined VHL epigenetic regulation in normal pregnancy and in preeclampsia, a pathology characterized by placental hypoxia. Design, Setting, and Participants Placentae were obtained from early-onset preeclampsia (n = 56; <34 weeks of gestation) and late-onset preeclampsia (n = 19; ≥34 weeks of gestation). Placentae from healthy normotensive age-matched preterm control (n = 43) and term control (n = 23) pregnancies were included as controls. Main Outcome Measure(s) We measured the activity of Jumonji domain containing protein 6 (JMJD6), a ferrous iron (Fe 2+)- and oxygen-dependent histone demethylase, and examined its function in the epigenetic control of VHL. Results JMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe 2+ bioavailability. Chromatin immunoprecipitation assays revealed decreased association of JMJD6 and its histone targets with the VHL promoter. Findings in preeclampsia were corroborated in a murine model of pharmacological hypoxia using FG-4592. Placentae from FG-4592-treated mice exhibited reduced VHL levels, accompanied by placental morphological alterations and reduced pup weights. Notably, Fe 2+ supplementation rescued JMJD6 histone demethylase activity in histone from E-PE and FG-4592-treated mice. Conclusions Our study uncovers epigenetic regulation of VHL and its functional consequences for altered oxygen and iron homeostasis in preeclampsia.