title: VariableDAXXgene methylation is a common feature of placental trophoblast differentiation, preeclampsia, and response to hypoxia.
abstract: Placental functioning relies on the appropriate differentiation of progenitor villous cytotrophoblasts (CTBs) into extravillous cytotrophoblasts (EVCTs), including invasive EVCTs, and the multinucleated syncytiotrophoblast (ST) layer. This is accompanied by a general move away from a proliferative, immature phenotype. Genome-scale expression studies have provided valuable insight into genes that are associated with the shift to both an invasive EVCT and ST phenotype, whereas genome-scale DNA methylation analysis has shown that differentiation to ST involves widespread methylation shifts, which are counteracted by low oxygen. In the current study, we sought to identify DNA methylation variation that is associated with transition from CTB to STin vitroand from a noninvasive to invasive EVCT phenotype after culture on Matrigel. Of the several hundred differentially methylated regions that were identified in each comparison, the majority showed a loss of methylation with differentiation. This included a large differentially methylated region (DMR) in the gene body of death domain-associated protein 6 (DAXX), which lost methylation during both CTB syncytialization to ST and EVCT differentiation to invasive EVCT. Comparison to publicly available methylation array data identified the same DMR as among the most consistently differentially methylated genes in placental samples from preeclampsia pregnancies. Of interest,in vitroculture of CTB or ST in low oxygen increases methylation in the same region, which correlates with delayed differentiation. Analysis of combined epigenomics signatures confirmedDAXXDMR as a likely regulatory element, and direct gene expression analysis identified a positive association between methylation at this site andDAXXexpression levels. The widespread dynamic nature ofDAXXmethylation in association with trophoblast differentiation and placenta-associated pathologies is consistent with an important role for this gene in proper placental development and function.-Novakovic, B., Evain-Brion, D., Murthi, P., Fournier, T., Saffery, R. Variable DAXX gene methylation is a common feature of placental trophoblast differentiation, preeclampsia, and response to hypoxia.
authors.affiliation: Cancer and Disease Epigenetics, Murdoch Children's Research Institute, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Boris
authors.initials: B
authors.lastname: Novakovic
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1139, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|PremUp Foundation, Paris, France.
authors.forename: Danièle
authors.initials: D
authors.lastname: Evain-Brion
authors.affiliation: Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia.|Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.
authors.forename: Padma
authors.initials: P
authors.lastname: Murthi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1139, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|PremUp Foundation, Paris, France.
authors.forename: Thiery
authors.initials: T
authors.lastname: Fournier
authors.affiliation: Cancer and Disease Epigenetics, Murdoch Children's Research Institute, Parkville, Victoria, Australia; richard.saffery@mcri.edu.au.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D019175:DNA Methylation / Q000502:physiology*; D057890:Epigenomics; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D055106:Genome-Wide Association Study; D006801:Humans; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000008:administration & dosage*; D010920:Placenta / Q000166:cytology; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D014327:Trophoblasts / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D010100:Oxygen
keywords: DNA methylation; Infinium HM450; placenta