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.

Keywords: :

• DNA methylation
• imprinted genes
• maternal factors
• twins
• developmental origins of health and disease (DOHaD)

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We wish to thank John Carlin, Clinical Epidemiology and Biostatistics Unit, MCRI, Mark Umstad, Royal Women’s Hospital, Melbourne, Euan Wallace, Monash Medical Centre, Melbourne and Mark Permezel, Mercy Hospital for Women, Melbourne for their contributions to establishing the PETS cohort; Sarah Healy, Tin Vaiano, Nicole Brookes, Jennifer Foord, Sheila Holland, Anne Krastev, Siva Illancheran and Joanne Mockler for recruitment and sample collection; Technical officer Anna Czajko, Study Coordinator Geraldine McIlroy, and all mothers and twins that participated in this study.

Financial Disclosures

This work was supported by grants from the Australian National Health and Medical Research Council [grant numbers 437015, 607358 to JMC and RS]; the Financial Markets Foundation for Children (grant number 032-2007); and the Victorian Government’s Operational Infrastructure Support Program. JMC and YJL would like to acknowledge financial support from the Murdoch Childrens Research Institute. The authors have no competing financial interests.

Supplemental Materials

Supplemental materials may be found here: http://www.landesbioscience.com/journals/epigenetics/article/25908