Dataset Information

Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus.

ABSTRACT: Intrauterine exposure to gestational diabetes mellitus (GDM) is linked to development of hypertension, obesity, and type 2 diabetes in children. Our previous studies determined that endothelial colony-forming cells (ECFCs) from neonates exposed to GDM exhibit impaired function. The current goals were to identify aberrantly expressed genes that contribute to impaired function of GDM-exposed ECFCs and to evaluate for evidence of altered epigenetic regulation of gene expression. Genome-wide mRNA expression analysis was conducted on ECFCs from control and GDM pregnancies. Candidate genes were validated by quantitative RT-PCR and Western blotting. Bisulfite sequencing evaluated DNA methylation of placenta-specific 8 (PLAC8). Proliferation and senescence assays of ECFCs transfected with siRNA to knockdown PLAC8 were performed to determine functional impact. Thirty-eight genes were differentially expressed between control and GDM-exposed ECFCs. PLAC8 was highly expressed in GDM-exposed ECFCs, and PLAC8 expression correlated with maternal hyperglycemia. Methylation status of 17 CpG sites in PLAC8 negatively correlated with mRNA expression. Knockdown of PLAC8 in GDM-exposed ECFCs improved proliferation and senescence defects. This study provides strong evidence in neonatal endothelial progenitor cells that GDM exposure in utero leads to altered gene expression and DNA methylation, suggesting the possibility of altered epigenetic regulation.

SUBMITTER: Blue EK

PROVIDER: S-EPMC4477353 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus.

Blue Emily K EK Sheehan BreAnn M BM Nuss Zia V ZV Boyle Frances A FA Hocutt Caleb M CM Gohn Cassandra R CR Varberg Kaela M KM McClintick Jeanette N JN Haneline Laura S LS

Diabetes 20150226 7

Intrauterine exposure to gestational diabetes mellitus (GDM) is linked to development of hypertension, obesity, and type 2 diabetes in children. Our previous studies determined that endothelial colony-forming cells (ECFCs) from neonates exposed to GDM exhibit impaired function. The current goals were to identify aberrantly expressed genes that contribute to impaired function of GDM-exposed ECFCs and to evaluate for evidence of altered epigenetic regulation of gene expression. Genome-wide mRNA ex ...[more]

PMID: 25720387

Similar Datasets

Project description:BackgroundThe micronutrient iodine is essential for a healthy intrauterine environment and is required for optimal fetal growth and neurodevelopment. Evidence linking urinary iodine concentrations, which mainly reflects short-term iodine intake, to gestational diabetes mellitus (GDM) is inconclusive. Although the placental concentrations would better reflect the long-term gestational iodine status, no studies to date have investigated the association between the placental iodine load and the risk at GDM. Moreover, evidence is lacking whether placental iodine could play a role in biomarkers of insulin resistance and β-cell activity.MethodsWe assessed the incidence of GDM between weeks 24 and 28 of gestation for 471 mother-neonate pairs from the ENVIRONAGE birth cohort. In placentas, we determined the iodine concentrations. In maternal and cord blood, we measured the insulin concentrations, the Homeostasis Model Assessment (HOMA) for insulin resistance (IR) index, and β-cell activity. Logistic regression was used to estimate the odds ratios (OR) of GDM, and the population attributable factor (PAF) was calculated. Generalized linear models estimated the changes in insulin, HOMA-IR, and β-cell activity for a 5 μg/kg increase in placental iodine.ResultsHigher placental iodine concentrations decreased the risk at GDM (OR = 0.82; 95%CI 0.72 to 0.93; p = 0.003). According to the PAF, 54.2% (95%CI 11.4 to 82.3%; p = 0.0006) of the GDM cases could be prevented if the mothers of the lowest tertile of placental iodine would have placental iodine levels as those belonging to the highest tertile. In cord blood, the plasma insulin concentration was inversely associated with the placental iodine load (β = - 4.8%; 95%CI - 8.9 to - 0.6%; p = 0.026).ConclusionsHigher concentrations of placental iodine are linked with a lower incidence of GDM. Moreover, a lower placental iodine load is associated with an altered plasma insulin concentration, HOMA-IR index, and β-cell activity. These findings postulate that a mild-to-moderate iodine deficiency could be linked with subclinical and early-onset alterations in the normal insulin homeostasis in healthy pregnant women. Nevertheless, the functional link between gestational iodine status and GDM warrants further research.

Project description:Gestational diabetes mellitus (GDM) is a unique form of glucose intolerance, in that it is transient and solely occurs in pregnancy. Pregnancies with GDM are at high risk of developing preeclampsia (PE), a leading cause of fetal and maternal morbidity or mortality. Since PE is associated with excessive activation of circulatory neutrophils and occurrence of neutrophil extracellular traps (NETs) in affected placentae, we examined these features in cases with GDM, as this could be a feature linking the two conditions. Our data indicate that neutrophil activity is indeed altered in GDM, exhibiting pronounced activation and spontaneous generation of NETs by isolated neutrophils in in vitro culture. In this manner, GDM may similarly affect neutrophil behavior and NET formation as witnessed in other forms of diabetes, with the addition of the physiological changes mediated by pregnancy. Since circulatory TNF-α levels are elevated in cases with GDM, a feature also observed in this study, we examined whether this pro-inflammatory cytokine contributed to neutrophil activation. By using infliximab, a clinically utilized TNF-α antagonist, we observed that the pro-NETotic effect of GDM sera was significantly reduced. We also detected pronounced neutrophil infiltrates in placentae from GDM cases. The occurrence of NETs in these tissues is suggested by the extracellular co-localization of citrullinated histones and myeloperoxidase. In addition, elevated neutrophil elastase (NE) mRNA and active enzymatic protein were also detected in such placentae. This latter finding could be important in the context of previous studies in cancer or diabetes model systems, which indicated that NE liberated from infiltrating neutrophils enters surrounding cells, altering cell signaling by the degradation of IRS1. These findings could potentiate the underlying inflammatory response process in GDM and possibly open an avenue for the therapeutic interventions in gestational hyperglycemia.

Dataset Information

Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus.

Publications

Epigenetic Regulation of Placenta-Specific 8 Contributes to Altered Function of Endothelial Colony-Forming Cells Exposed to Intrauterine Gestational Diabetes Mellitus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets