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Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes.

ABSTRACT: Microorganisms in the placenta have been linked to adverse pregnancy outcomes as well as neonatal illness. Inflammation in the placenta has been identified as a contributing factor in this association, but the underlying biological mechanisms are not yet fully understood. The placental epigenome may serve as an intermediate between placental microbes and inflammation, contributing to adverse outcomes in the offspring. In the present study, genome-wide DNA methylation (n = 486,428 CpG sites) of 84 placentas was analyzed in relation to 16 species of placental microorganisms using samples collected from the Extremely Low Gestation Age Newborns (ELGAN) cohort. A total of n = 1,789 CpG sites, corresponding to n = 1,079 genes, displayed differential methylation (q<0.1) in relation to microorganisms. The altered genes encode for proteins that are involved in immune/inflammatory responses, specifically the NF-κB signaling pathway. These data support bacteria-dependent epigenetic patterning in the placenta and provide potential insight into mechanisms that associate the presence of microorganisms in the placenta to pregnancy and neonatal outcomes. This study lays the foundation for investigations of the placental microbiome and its role in placental function.

SUBMITTER: Tomlinson MS

PROVIDER: S-EPMC5730116 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes.

Tomlinson Martha Scott MS Bommarito Paige A PA Martin Elizabeth M EM Smeester Lisa L Fichorova Raina N RN Onderdonk Andrew B AB Kuban Karl C K KCK O'Shea T Michael TM Fry Rebecca C RC

PloS one 20171214 12

Microorganisms in the placenta have been linked to adverse pregnancy outcomes as well as neonatal illness. Inflammation in the placenta has been identified as a contributing factor in this association, but the underlying biological mechanisms are not yet fully understood. The placental epigenome may serve as an intermediate between placental microbes and inflammation, contributing to adverse outcomes in the offspring. In the present study, genome-wide DNA methylation (n = 486,428 CpG sites) of 8 ...[more]

PMID: 29240761

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Project description:BackgroundInfants born extremely premature are at increased risk for health complications later in life for which neonatal inflammation may be a contributing biological driver. Placental CpG methylation provides mechanistic information regarding the relationship between prenatal epigenetic programming, prematurity, neonatal inflammation, and later-in-life health.MethodsWe contrasted CpG methylation in the placenta and neonatal blood spots in relation to neonatal inflammation in the Extremely Low Gestational Age Newborn (ELGAN) cohort. Neonatal inflammation status was based on the expression of six inflammation-related proteins, assessed as (1) day-one inflammation (DOI) or (2) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 postnatal weeks). Epigenome-wide CpG methylation was assessed in 354 placental samples and 318 neonatal blood samples.ResultsPlacental CpG methylation displayed the strongest association with ISSI (48 CpG sites) but was not associated with DOI. This was in contrast to CpG methylation in blood spots, which was associated with DOI (111 CpG sites) and not with ISSI (one CpG site).ConclusionsPlacental CpG methylation was strongly associated with ISSI, a measure of inflammation previously linked to later-in-life cognitive impairment, while day-one neonatal blood methylation was associated with DOI.ImpactNeonatal inflammation increases the risk of adverse later-life outcomes, especially in infants born extremely preterm. CpG methylation in the placenta and neonatal blood spots were evaluated in relation to neonatal inflammation assessed via circulating proteins as either (i) day-one inflammation (DOI) or (ii) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 weeks). Tissue specificity was observed in epigenetic-inflammatory relationships: placental CpG methylation was associated with ISSI, neonatal blood CpG methylation was associated with DOI. Supporting the placental origins of disease framework, placental epigenetic patterns are associated with a propensity for ISSI in neonates.

Project description:Background: Maternal diet during pregnancy has been shown to influence the child neuro-developmental outcomes. Studies examining effects of dietary patterns on offspring behavior are sparse. Objective: Determine if maternal adherence to a Mediterranean diet is associated with child behavioral outcomes assessed early in life, and to evaluate the role of differentially methylated regions (DMRs) regulating genomically imprinted genes in these associations. Methods: Among 325 mother/infant pairs, we used regression models to evaluate the association between tertiles of maternal periconceptional Mediterranean diet adherence (MDA) scores derived from a Food Frequency Questionnaire, and social and emotional scores derived from the Infant Toddler Social and Emotional Assessment (ITSEA) questionnaire in the second year of life. Methylation of nine genomically imprinted genes was measured to determine if MDA was associated with CpG methylation. Results: Child depression was inversely associated with maternal MDA (Bonferroni-corrected p = 0.041). While controlling for false-discovery, compared to offspring of women with the lowest MDA tertile, those with MDA scores in middle and high MDA tertiles had decreased odds for atypical behaviors [OR (95% CI) = 0.40 (0.20, 0.78) for middle and 0.40 (0.17, 0.92) for highest tertile], for maladaptive behaviors [0.37 (0.18, 0.72) for middle tertile and 0.42 (0.18, 0.95) for highest tertile] and for an index of autism spectrum disorder behaviors [0.46 (0.23, 0.90) for middle and 0.35 (0.15, 0.80) for highest tertile]. Offspring of women with the highest MDA tertile were less likely to exhibit depressive [OR = 0.28 (0.12, 0.64)] and anxiety [0.42 (0.18, 0.97)] behaviors and increased odds of social relatedness [2.31 (1.04, 5.19)] behaviors when compared to low MDA mothers. Some associations varied by sex. Perinatal MDA score was associated with methylation differences for imprinted control regions of PEG10/SGCE [females: Beta (95% CI) = 1.66 (0.52, 2.80) - Bonferroni-corrected p = 0.048; males: -0.56 (-1.13, -0.00)], as well as both MEG3 and IGF2 in males [0.97 (0.00, 1.94)] and -0.92 (-1.65, -0.19) respectively. Conclusion: In this ethnically diverse cohort, maternal adherence to a Mediterranean diet in early pregnancy was associated with favorable neurobehavioral outcomes in early childhood and with sex-dependent methylation differences of MEG3, IGF2, and SGCE/PEG10 DMRs.

Project description:Placental cortisol is inactivated in normotensive pregnancies, but is frequently present in pre-eclampsia associated placentae. Since glucocorticoids are strongly associated with the programming of long-term health, we assessed DNA methylation of genes involved in cortisol signalling and bioavailability, and hormonal signalling in the placenta of normotensive and hypertensive pregnancies. Candidate genes/CpG sites were selected through analysis of Illumina Infinium HumanMethylation450 BeadChip array data on control (n?=?19) and early onset pre-eclampsia (EOPET; n?=?19) placental samples. DNA methylation was further quantified by bisulfite pyrosequencing in a larger cohort of control (n?=?111) cases, in addition to EOPET (n?=?19), late onset pre-eclampsia (LOPET; n?=?18) and normotensive intrauterine growth restriction (nIUGR; n?=?13) cases. DNA methylation (percentage points) was increased at CpG sites within genes encoding the glucocorticoid receptor (NR3C1 exon 1D promoter; +8.46%; P<0.01) and corticotropin releasing hormone (CRH) binding protein (CRHBP intron 3; +9.14%; P<0.05), and decreased within CRH (5' UTR; -4.30%; P?=?0.11) in EOPET-associated placentae, but not in LOPET nor nIUGR cases, compared to controls. Differential DNA methylation was not observed among groups at the 11?-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene promoter. Significant hypomethylation was observed in pre-eclampsia but not nIUGR placentae for steroidogenic genes, including CYP11A1 (exon1; EOPET; -9.66%; P<0.00001, and LOPET; -5.77%; P<0.001), 3?-hydroxy-delta-5-steroid dehydrogenase type 1 (HSD3B1 exon 2; EOPET; -12.49%; P<0.00001, and LOPET; -6.88%; P<0.001), TEA domain family member 3 (TEAD3 intron 1; EOPET; -12.56%; P<0.00001) and CYP19 (placental-specific exon 1.1 promoter; EOPET; -10.62%, P<0.0001). These data represent dysregulation of the placental epigenome in pre-eclampsia related to genes involved in maintaining the hormonal environment during pregnancy and highlights particular susceptibility in the early onset syndrome.

Project description:DNA methylation, as an epigenetic mechanism, has a vital role in heart development. An increasing number of studies have investigated aberrant DNA methylation in pediatric or adult heart samples from patients with congenital heart defects (CHD). Placenta tissue, umbilical cord blood, or newborn blood have also been used to detect DNA methylation biomarkers for CHD. However, few studies have compared the methylation levels in fetal heart tissue with cardiac defects with that in normal controls. The present study conducted an integrative whole-genome and CpG site-specific DNA methylation analysis of fetal heart samples from 17 isolated cardiac defect cases, 14 non-isolated cardiac defect cases, and 22 controls with normal hearts, using methylated DNA immunoprecipitation microarray and MassARRAY EpiTYPER assays. Expression of genes adjacent to differentially methylated regions (DMRs) was measured by RT-qPCR and western blot analysis. The results revealed that fetuses with cardiac defects presented global hypomethylation. Genomic analysis of DMRs revealed that a proportion of DMRs were located in exons (12.4%), distal intergenic regions (11.14%), and introns (8.97%). Only 55.7% of DMRs were observed at promoter regions. Functional enrichment analysis for genes adjacent to these DMRs revealed that hypomethylated genes were involved in embryonic heart tube morphogenesis and immune-related regulation functions. Intergenic hypermethylation of EGFR and solute carrier family 19 member 1 (SLC19A1), and intragenic hypomethylation of NOTCH1 were validated in fetal heart tissues with cardiac defects. Only SLC19A1 expression was significantly decreased at the mRNA level, while EGFR, NOTCH1, and SLC19A1 expression were all significantly decreased at the protein level. In conclusion, the present study demonstrated that fetal cardiac defects may be associated with alterations in regional and single CpG site methylation outside of promoter regions, resulting in differentiated expression of corresponding genes associated with heart development. These results present new insights into the epigenetic mechanisms underlying abnormal heart development.

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Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes.

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Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes.

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