Unknown,Transcriptomics,Genomics,Proteomics

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Perturbed neonatal size is associated with differential DNA methylation and gene expression in human placentas

ABSTRACT: Fetal growth in utero is affected by both inherent genetic programming in combination with environmental factors, such as maternal health and nutrition. Epidemiologic data in growth-altered fetuses, either growth-restricted (IUGR) or large for gestational age (LGA), demonstrate compelling evidence that these fetuses are at increased risk for cardiovascular and metabolic disease in adulthood. In this study, we used RRBS to examine genome wide DNA methylation variation in placental samples from offspring born IUGR, LGA, and appropriate for gestational age (AGA). We identified almost 200 differentially methylated genes among these groups. Among these genes, the differentially methylated regions were disproportionately located in transcription-regulatory regions such as promoters. Our results suggest that the gene expression and methylation state of the human placenta are related and sensitive to the intrauterine environment. We profiled DNA methylation for 17 human placentas, in which 5 were from LGA, 6 from IUGR and 6 from AGA placentas as controls

ORGANISM(S): Homo sapiens

SUBMITTER: Wen-Wei Liao

PROVIDER: E-GEOD-70364 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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.