Evidence for widespread changes in promoter methylation profile in human placenta in response to increasing gestational age and environmental/stochastic factors.
BACKGROUND
The human placenta facilitates the exchange of nutrients, gas and waste between the fetal and maternal circulations. It also protects the fetus from the maternal immune response. Due to its role at the feto-maternal interface, the placenta is subject to many environmental exposures that can potentially alter its epigenetic profile. Previous studies have reported gene expression differences in placenta over gestation, as well as inter-individual variation in expression of some genes. However, the factors contributing to this variation in gene expression remain poorly understood.


RESULTS
In this study, we performed a genome-wide DNA methylation analysis of gene promoters in placenta tissue from three pregnancy trimesters. We identified large-scale differences in DNA methylation levels between first, second and third trimesters, with an overall progressive increase in average methylation from first to third trimester. The most differentially methylated genes included many immune regulators, reflecting the change in placental immuno-modulation as pregnancy progresses. We also detected increased inter-individual variation in the third trimester relative to first and second, supporting an accumulation of environmentally induced (or stochastic) changes in DNA methylation pattern. These highly variable genes were enriched for those involved in amino acid and other metabolic pathways, potentially reflecting the adaptation of the human placenta to different environments.


CONCLUSIONS
The identification of cellular pathways subject to drift in response to environmental influences provide a basis for future studies examining the role of specific environmental factors on DNA methylation pattern and placenta-associated adverse pregnancy outcomes.
Cancer, Disease and Developmental Epigenetics, Murdoch Childrens Research Institute, Royal Children's Hospital and Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia.
Boris
B
Novakovic
Ryan K
RK
Yuen
Lavinia
L
Gordon
Maria S
MS
Penaherrera
Andrew
A
Sharkey
Ashley
A
Moffett
Jeffrey M
JM
Craig
Wendy P
WP
Robinson
Richard
R
Saffery
D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D004777:Environment; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D015894:Genome, Human; D005865:Gestational Age; D006801:Humans; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D011263:Pregnancy Trimester, Third; D011401:Promoter Regions, Genetic; D013269:Stochastic Processes