title: Epigenetic regulation of human placental function and pregnancy outcome: considerations for causal inference.
abstract: Epigenetic mechanisms, often defined as regulating gene activity independently of underlying DNA sequence, are crucial for healthy development. The sum total of epigenetic marks within a cell or tissue (the epigenome) is sensitive to environmental influence, and disruption of the epigenome in utero has been associated with adverse pregnancy outcomes. Not surprisingly, given its multifaceted functions and important role in regulating pregnancy outcome, the placenta shows unique epigenetic features. Interestingly however, many of these are only otherwise seen in human malignancy (the pseudomalignant placental epigenome). Epigenetic variation in the placenta is now emerging as a candidate mediator of environmental influence on placental functioning and a key regulator of pregnancy outcome. However, replication of findings is generally lacking, most likely due to small sample sizes and a lack of standardization of analytical approaches. Defining DNA methylation "signatures" in the placenta associated with maternal and fetal outcomes offers tremendous potential to improve pregnancy outcomes, but care must be taken in interpretation of findings. Future placental epigenetic research would do well to address the issues present in epigenetic epidemiology more generally, including careful consideration of sample size, potentially confounding factors, issues of tissue heterogeneity, reverse causation, and the role of genetics in modulating epigenetic profile. The importance of animal or in vitro models in establishing a functional role of epigenetic variation identified in human beings, which is key to establishing causation, should not be underestimated.
authors.affiliation: Cancer and Disease Epigenetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.
authors.forename: Vania
authors.initials: V
authors.lastname: Januar
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Desoye
authors.affiliation: Cancer and Disease Epigenetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia.
authors.forename: Boris
authors.initials: B
authors.lastname: Novakovic
authors.affiliation: Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria.
authors.forename: Silvija
authors.initials: S
authors.lastname: Cvitic
authors.affiliation: Cancer and Disease Epigenetics, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Australia; Department of Pediatrics, University of Melbourne, Parkville, Australia. Electronic address: richard.saffery@mcri.edu.au.
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
mesh_terms: D001755:Blastocyst; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D018392:Genomic Imprinting; D006801:Humans; D010920:Placenta / Q000502:physiology*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000235:genetics*; D011256:Pregnancy Outcome / Q000235:genetics*; D012737:Sex Factors
keywords: DNA methylation; Developmental Origins of Health and Disease; confounding; development; epigenetics; epigenome; fetal programming; gestational age; gestational diabetes; intrauterine growth restriction; placenta; preeclampsia; pseudomalignant; reverse causation; trophoblast