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Promoter methylomes of monochorionic twin placentas reveal intrauterine growth restriction specific methylation profiles

ABSTRACT: Intrauterine growth restriction (IUGR) is one of the most common adverse pregnancy outcomes with high risk of perinatal morbidity and mortality, and affects up to 7% of pregnancies. Here, seven pairs of placentas were employed for whole genomic promoter DNA methylation profiling and some of the candidate differentially methylated promoters were further validated in additional twelve pairs of samples. Consistent with previous report, our results further indicated that IUGR associated placentas harbored a distinct promoter DNA hypomethylation pattern and the result was further confirmed byultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS)

ORGANISM(S): Homo sapiens

PROVIDER: GSE67377 | GEO | 2015/08/31

SECONDARY ACCESSION(S): PRJNA279799

REPOSITORIES: GEO

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Project description:Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies and often results in short- and long- term sequelae for offspring, including risk for adult cardiovascular disease (CVD). The mechanisms underlying IUGR are poorly understood, though poor blood flow and oxygen/nutrient provision to the IUGR fetus are thought to be the common endpoints of disease. Though several animal models of IUGR exist, few demonstrate later phenotypes of CVD despite a large body of evidence in humans linking IUGR and adult CVD onset. We thus hypothesized that in murine pregnancy, maternal late gestational hypoxia (LG-H) exposure resulting in IUGR would result in (1) adult phenotypes of CVD in hypoxia-exposed offspring, and (2) the placental transcriptome will demonstrate alterations that can be linked to risk of later disease. After subjecting pregnant mice to hypoxia (10.5% oxygen) from gestational day (GD) 14.5 to 18.5, we collected placentas at GD19. We examined RNA isolated from these placentas to perform RNA sequencing and analysis. Functional gene and cluster-based analysis suggest multiple changes in structural and functional genes important for placental health, with the top dysregulation involving vascular and metabolic pathways. Concordantly, a ~ 10% decrease in birthweights and ~30% decrease in litter size after LG-H (p<0.05) was observed, suggesting an environment of placental insufficiency. We also found that offspring exposed in-utero to LG-H exhibit CVD at 4 months of age, with males being worse than females, supporting developmental programming. Specifically, males exhibit increased body weight and an enlarged heart size, whereas both males and females develop hypertension, elevated abdominal fat, elevated leptin and elevated total cholesterol levels with aging. In summary, LG-H exposure in the pregnant mouse mimics human placental insufficiency related IUGR. The placentas of these exposed fetuses demonstrate a transcriptional response to the stressor of gestational hypoxia and predicts cardiovascular and metabolic effects that culminate into hypertension and adiposity with dyslipidemia.

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Promoter methylomes of monochorionic twin placentas reveal intrauterine growth restriction specific methylation profiles

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