The Dynamic Role of Jumonji C Domain Containing Protein 6 in Placental Development and Disease

Perturbations in oxygen sensing are a defining feature of placental-associated pathologies such as preeclampsia, a serious disorder of pregnancy. Preeclamptic placentae have markedly elevated levels of Hypoxia Inducible Factor 1Îą (HIF1A), a master regulator of oxygen homeostasis. Mounting evidence implicates a family of Fe2+ and oxygen-dependent Jumonji C domain containing enzymes (JMJDs) as mediators of the epigenetic code and hypoxic gene expression. While several JMJDs are induced in hypoxia, their role in pregnancy remains unclear. The goal of this study was to characterize JMJD6 function in the placenta in physiological and pathological conditions, and unravel its regulatory relationship with von Hippel Lindau tumour suppressor (VHL), a key executor of the cellular hypoxic response. JMJD6 expression inversely correlated with changes in oxygen tension during placental development, while JMJD6 protein and mRNA were significantly elevated in low oxygen and in early-onset preeclamptic (E-PE) placentae. In vitro demethylation assays revealed that optimal JMJD6-dependent demethylation of its histone targets, H3R2me2s and H4R3me2s, occurred in normoxia, and this was impaired in E-PE placentae due to a hypoxia-iron imbalance. In cytotrophoblast cells, JMJD6 is a positive regulator of VHL gene expression in normoxia. Accordingly, JMJD6 histone targets in E-PE placentae showed marked reductions in their association with VHL promoter regions. Independent of VHL gene regulation, JMJD6 also controlled VHL protein stability through lysyl hydroxylation and promoting its SUMO1-dependent SUMOylation. Importantly, the Jumonji C catalytic domain was found to be indispensable in executing both functions of JMJD6. In summary, these data signify a novel function for JMJD6 as an oxygen sensor in the human placenta, exerting a dual role in regulating VHL gene and protein. Uncovering epigenetic oxygen sensing mechanisms controlling HIF1A is crucial for defining the unique molecular signature of preeclampsia, which may ultimately translate to molecular-based diagnosis and therapy.Ph.D