title: Association of maternal and nutrient supply line factors with DNA methylation at the imprinted IGF2/H19 locus in multiple tissues of newborn twins.
abstract: Epigenetic events are crucial for early development, but can be influenced by environmental factors, potentially programming the genome for later adverse health outcomes. The insulin-like growth factor 2 (IGF2)/H19 locus is crucial for prenatal growth and the epigenetic state at this locus is environmentally labile. Recent studies have implicated maternal factors, including folate intake and smoking, in the regulation of DNA methylation at this locus, although data are often conflicting in the direction and magnitude of effect. Most studies have focused on single tissues and on one or two differentially-methylated regions (DMRs) regulating IGF2/H19 expression. In this study, we investigated the relationship between multiple shared and non-shared gestational/maternal factors and DNA methylation at four IGF2/H19 DMRs in five newborn cell types from 67 pairs of monozygotic and 49 pairs of dizygotic twins. Data on maternal and non-shared supply line factors were collected during the second and third trimesters of pregnancy and DNA methylation was measured via mass spectrometry using Sequenom MassArray EpiTyper analysis. Our exploratory approach showed that the site of umbilical cord insertion into the placenta in monochorionic twins has the strongest positive association with methylation in all IGF2/H19 DMRs (p<0.05). Further, evidence for tissue- and locus-specific effects were observed, emphasizing that responsiveness to environmental exposures in utero cannot be generalized across genes and tissues, potentially accounting for the lack of consistency in previous findings. Such complexity in responsiveness to environmental exposures in utero has implications for all epigenetic studies investigating the developmental origins of health and disease.
authors.affiliation: Department of Paediatrics; University of Melbourne; Parkville, VIC Australia; Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Yuk Jing
authors.initials: YJ
authors.lastname: Loke
authors.affiliation: Clinical Epidemiology and Biostatistics Unit; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia; Department of Mathematics and Statistics; La Trobe University; Melbourne, VIC Australia.
authors.forename: John C
authors.initials: JC
authors.lastname: Galati
authors.affiliation: Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Ruth
authors.initials: R
authors.lastname: Morley
authors.affiliation: Department of Paediatrics; University of Melbourne; Parkville, VIC Australia; Cancer, Disease and Developmental Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Eric Ji-Hoon
authors.initials: EJ
authors.lastname: Joo
authors.affiliation: Department of Paediatrics; University of Melbourne; Parkville, VIC Australia; Cancer, Disease and Developmental Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Boris
authors.initials: B
authors.lastname: Novakovic
authors.affiliation: Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Blaise
authors.initials: B
authors.lastname: Weinrich
authors.affiliation: Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Carson
authors.affiliation: Hjelt Institute; Department of Public Health; University of Helsinki; Helsinki, Finland.
authors.forename: Miina
authors.initials: M
authors.lastname: Ollikainen
authors.affiliation: Cancer, Disease and Developmental Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Hong-Kiat
authors.initials: HK
authors.lastname: Ng
authors.affiliation: Department of Paediatrics; University of Melbourne; Parkville, VIC Australia; Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Roberta
authors.initials: R
authors.lastname: Andronikos
authors.affiliation: Department of Paediatrics; University of Melbourne; Parkville, VIC Australia; Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Nur Khairunnisa Abdul
authors.initials: NK
authors.lastname: Aziz
authors.affiliation: Department of Paediatrics; University of Melbourne; Parkville, VIC Australia; Cancer, Disease and Developmental Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Saffery
authors.affiliation: Department of Paediatrics; University of Melbourne; Parkville, VIC Australia; Early Life Epigenetics Group; Murdoch Childrens Research Institute (MCRI); Royal Children's Hospital; Parkville, VIC Australia.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Craig
mesh_terms: D019175:DNA Methylation; D016640:Diabetes, Gestational / Q000235:genetics / Q000378:metabolism; D005260:Female; D056426:Genetic Loci; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008297:Male; D009928:Organ Specificity; D011247:Pregnancy; D039401:Prenatal Nutritional Physiological Phenomena; D062085:RNA, Long Noncoding / Q000235:genetics*; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic
chemical_list: C094335:H19 long non-coding RNA; C035170:IGF2 protein, human; D062085:RNA, Long Noncoding; D007335:Insulin-Like Growth Factor II
keywords: DNA methylation; developmental origins of health and disease (DOHaD); imprinted genes; maternal factors; twins
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