Amnion as a surrogate tissue reporter of the effects of maternal preeclampsia on the fetus.
BACKGROUND
Preeclampsia, traditionally characterized by high blood pressure and proteinuria, is a common pregnancy complication, which affects 2-8 % of all pregnancies. Although children born to women with preeclampsia have a higher risk of hypertension in later life, the mechanism of this increased risk is unknown. DNA methylation is an epigenetic modification that has been studied as a mediator of cellular memory of adverse exposures in utero. Since each cell type in the body has a unique DNA profile, cell subtype composition is a major confounding factor in studies of tissues with heterogeneous cell types. The best way to avoid this confounding effect is by using purified cell types. However, using purified cell types in large cohort translational studies is difficult. The amnion, the inner layer of the fetal membranes of the placenta, is derived from the epiblast and consists of two cell types, which are easy to isolate from the delivered placenta. In this study, we demonstrate the value of using amnion samples for DNA methylation studies, revealing distinctive patterns between fetuses exposed to proteinuria or hypertension and fetuses from normal pregnancies.


RESULTS
We performed a genome-wide DNA methylation analysis, HpaII tiny fragment Enrichment by Ligation-mediated PCR (HELP)-tagging, on 62 amnion samples from the placentas of uncomplicated, normal pregnancies and from those with complications of preeclampsia or hypertension. Using a regression model approach, we found 123, 85, and 99 loci with high-confidence hypertension-associated, proteinuria-associated, and hypertension- and proteinuria-associated DNA methylation changes, respectively. A gene ontology analysis showed DNA methylation changes to be selecting genes with different biological processes in exposure status. We also found that these differentially methylated regions overlap loci previously reported as differentially methylated regions in preeclampsia.


CONCLUSIONS
Our findings support prior observations that preeclampsia is associated with changes of DNA methylation near genes that have previously been found to be dysregulated in preeclampsia. We propose that amniotic membranes represent a valuable surrogate fetal tissue on which to perform epigenome-wide association studies of adverse intrauterine conditions.
Center for Epigenomics, Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA.
Masako
0000-0003-0605-9225
M
Suzuki
Center for Epigenomics, Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA ; Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Minamikogushi 1-1-1, Ube, 755-8505 Japan.
Ryo
R
Maekawa
Center for Epigenomics, Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA.
Nicole E
NE
Patterson
Center for Epigenomics, Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA.
David M
DM
Reynolds
Center for Epigenomics, Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA.
Brent R
BR
Calder
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Jamaica, NY 11439 USA ; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461 USA ; Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Price 322, Bronx, NY 10461 USA.
Sandra E
SE
Reznik
Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Price 322, Bronx, NY 10461 USA.
Hye J
HJ
Heo
Department of Obstetrics and Gynecology and Women's Health, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Price 322, Bronx, NY 10461 USA.
Francine Hughes
FH
Einstein
Center for Epigenomics, Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA.
John M
JM
Greally
D000650:Amnion / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012044:Regression Analysis
Amnion; DNA methylation; Genome-wide; HELP-tagging; Hypertension; Preeclampsia; Pregnancy; Sodium bisulfite