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Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment.

ABSTRACT: Early life adversity, including adverse gestational and postpartum maternal environment, is a contributing factor in the development of autism, attention deficit hyperactivity disorder (ADHD), anxiety and depression but little is known about the underlying molecular mechanism. In a model of gestational maternal adversity that leads to innate anxiety, increased stress reactivity and impaired vocal communication in the offspring, we asked if a specific DNA methylation signature is associated with the emergence of the behavioral phenotype. Genome-wide DNA methylation analyses identified 2.3% of CpGs as differentially methylated (that is, differentially methylated sites, DMSs) by the adverse environment in ventral-hippocampal granule cells, neurons that can be linked to the anxiety phenotype. DMSs were typically clustered and these clusters were preferentially located at gene bodies. Although CpGs are typically either highly methylated or unmethylated, DMSs had an intermediate (20-80%) methylation level that may contribute to their sensitivity to environmental adversity. The adverse maternal environment resulted in either hyper or hypomethylation at DMSs. Clusters of DMSs were enriched in genes that encode cell adhesion molecules and neurotransmitter receptors; some of which were also downregulated, indicating multiple functional deficits at the synapse in adversity. Pharmacological and genetic evidence links many of these genes to anxiety.

SUBMITTER: Oh JE

PROVIDER: S-EPMC3566713 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment.

Oh J-E JE Chambwe N N Klein S S Gal J J Andrews S S Gleason G G Shaknovich R R Melnick A A Campagne F F Toth M M

Translational psychiatry 20130122

Early life adversity, including adverse gestational and postpartum maternal environment, is a contributing factor in the development of autism, attention deficit hyperactivity disorder (ADHD), anxiety and depression but little is known about the underlying molecular mechanism. In a model of gestational maternal adversity that leads to innate anxiety, increased stress reactivity and impaired vocal communication in the offspring, we asked if a specific DNA methylation signature is associated with ...[more]

PMID: 23340501

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Project description:AIMS/HYPOTHESIS:Individuals exposed to maternal diabetes in utero are more likely to develop metabolic and cardiovascular diseases later in life. This may be partially attributable to epigenetic regulation of gene expression. We performed an epigenome-wide association study to examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes during the pregnancy (OMD) compared with offspring of mothers with no diabetes during the pregnancy (OMND). METHODS:DNA methylation was measured in peripheral blood using the Illumina HumanMethylation450K BeadChip. A total of 423,311 CpG sites were analysed in 388 Pima Indian individuals, mean age at examination was 13.0 years, 187 of whom were OMD and 201 were OMND. Differences in methylation between OMD and OMND were assessed. RESULTS:Forty-eight differentially methylated CpG sites (with an empirical false discovery rate ?0.05), mapping to 29 genes and ten intergenic regions, were identified. The gene with the strongest evidence was LHX3, in which six CpG sites were hypermethylated in OMD compared with OMND (p???1.1?×?10-5). Similarly, a CpG near PRDM16 was hypermethylated in OMD (1.1% higher, p?=?5.6?×?10-7), where hypermethylation also predicted future diabetes risk (HR 2.12 per SD methylation increase, p?=?9.7?×?10-5). Hypermethylation near AK3 and hypomethylation at PCDHGA4 and STC1 were associated with exposure to diabetes in utero (AK3: 2.5% higher, p?=?7.8?×?10-6; PCDHGA4: 2.8% lower, p?=?3.0?×?10-5; STC1: 2.9% lower, p?=?1.6?×?10-5) and decreased insulin secretory function among offspring with normal glucose tolerance (AK3: 0.088 SD lower per SD of methylation increase, p?=?0.02; PCDHGA4: 0.08 lower SD per SD of methylation decrease, p?=?0.03; STC1: 0.072 SD lower per SD of methylation decrease, p?=?0.05). Seventeen CpG sites were also associated with BMI (p???0.05). Pathway analysis of the genes with at least one differentially methylated CpG (p?<?0.005) showed enrichment for three relevant biological pathways. CONCLUSIONS/INTERPRETATION:Intrauterine exposure to diabetes can affect methylation at multiple genomic sites. Methylation status at some of these sites can impair insulin secretion, increase body weight and increase risk of type 2 diabetes.

Project description:BackgroundSingle nucleotide polymorphisms (SNPs) may influence arsenic methylation efficiency, affecting arsenic metabolism. Whether gene-environment interactions affect arsenic metabolism during pregnancy remains unclear, which may have implications for pregnancy outcomes.ObjectiveWe aimed to investigate main effects as well as potential SNP-arsenic interactions on arsenic methylation efficiency in pregnant women.MethodWe recruited 1613 pregnant women in Bangladesh, and collected two urine samples from each participant, one at 4-16 weeks, and the second at 21-37 weeks of pregnancy. We determined the proportions of each arsenic metabolite [inorganic As (iAs)%, monomethylarsonic acid (MMA)%, and dimethylarsinic acid (DMA)%] from the total urinary arsenic level of each sample. A panel of 63 candidate SNPs was selected for genotyping based on their reported associations with arsenic metabolism (including in As3MT, N6AMT1, and GSTO2 genes). We used linear regression models to assess the association between each SNP and DMA% with an additive allelic assumption, as well as SNP-arsenic interaction on DMA%. These analyses were performed separately for two urine collection time-points to capture differences in susceptibility to arsenic toxicity.ResultIntron variants for As3MT were associated with DMA%. rs9527 (β = -2.98%, PFDR = 0.008) and rs1046778 (β = 1.64%, PFDR = 0.008) were associated with this measure in the early gestational period; rs3740393 (β = 2.54%, PFDR = 0.002) and rs1046778 (β = 1.97%, PFDR = 0.003) in the mid-to-late gestational period. Further, As3MT, GSTO2, and N6AMT1 polymorphisms showed different effect sizes on DMA% conditional on arsenic exposure levels. However, SNP-arsenic interactions were not statistically significant after adjusting for false discovery rate (FDR). rs1048546 in N6AMT1 had the highest significance level in the SNP-arsenic interaction test during mid-to-late gestation (β = -1.8% vs. 1.4%, PGxE_FDR = 0.075). Finally, As3MT and As3MT/CNNM2 haplotypes were associated with DMA% at both time points.ConclusionWe found that not all genetic associations reported in arsenic methylation efficiency replicate in pregnant women. Arsenic exposure level has a limited effect in modifying the association between genetic variation and arsenic methylation efficiency.

Project description:BackgroundRacial and ethnic diversification of the physician and nurse workforce is recommended as a leverage point to address the impact of structural racism in maternal care, but empirical evidence supporting this recommendation is currently lacking.ObjectiveThis study aimed to assess the association between state-level registered nurse workforce racial and ethnic diversity and severe adverse maternal outcomes during childbirth.Study designThis population-based cross-sectional study analyzed 2017 US birth certificate data. Severe adverse maternal outcomes included eclampsia, blood transfusion, hysterectomy, or intensive care unit admission. Proportions of minoritized racial and ethnic registered nurses in each state were abstracted from the American Community Survey (5-year estimate, 2013-2017). This proportion was categorized into 3 terciles, with the first tercile corresponding to the lowest proportion and the third tercile corresponding to the highest proportion. Crude and adjusted odds ratios and 95% confidence intervals of severe adverse maternal outcomes associated with terciles of the state proportion of minoritized racial and ethnic nurses were estimated using logistic regression models.ResultsOf the 3,668,813 birth certificates studied, 29,174 recorded severe adverse maternal outcomes (79.5 per 10,000; 95% confidence interval, 78.6-80.4). The mean state proportion of minoritized racial and ethnic nurses was 22.1%, ranging from 3.3% in Maine to 68.2% in Hawaii. For White mothers, the incidence of severe adverse outcomes was 85.3 per 10,000 for those who gave births in states in the first tercile of the proportion of minoritized racial and ethnic nurses and 53.9 per 10,000 for those who gave birth in states in the third tercile (risk difference, -31.4 per 10,000; 95% confidence interval, -34.4 to -28.5). It corresponds to a 37% decreased risk of severe adverse maternal outcomes associated with giving birth in a state in the third tercile (crude odds ratio, 0.63; 95% confidence interval, 0.60-0.66). A decreased risk of severe adverse maternal outcomes was observed for Black mothers (crude odds ratio, 0.65; 95% confidence interval, 0.61-0.70), Hispanic mothers (crude odds ratio, 0.51; 95% confidence interval, 0.48-0.54), and Asian and Pacific Islander mothers (crude odds ratio, 0.65; 95% confidence interval, 0.58-0.72) but not for Native American mothers (crude odds ratio, 0.89; 95% confidence interval, 0.72-1.09) or mothers with >1 race (crude odds ratio, 1.44; 95% confidence interval, 0.72-1.09). After adjustment for patients and hospital characteristics, giving birth in states in the third tercile was associated with a reduced risk of severe adverse outcomes as follows: 32% for White mothers (adjusted odds ratio, 0.68; 95% confidence interval, 0.59-0.77), 20% for Black mothers (adjusted odds ratio, 0.80; 95% confidence interval, 0.65-0.99), 31% for Hispanic mothers (adjusted odds ratio, 0.69; 95% confidence interval, 0.58-0.82), and 50% for Asian and Pacific Islander mothers (adjusted odds ratio, 0.50; 95% confidence interval, 0.38-0.65). The associations of the proportion of minoritized racial and ethnic nurses with the risk of severe adverse maternal outcomes were not statistically significant for Native American mothers and more than 1 race mothers. Results were similar when blood transfusion was excluded from the outcome measure.ConclusionA diverse state registered nurse workforce was associated with a reduced risk of severe adverse maternal outcomes during childbirth.

Project description:BackgroundThe role of an adverse maternal environment (AME) in conjunction with a postweaning Western diet (WD) in the development of nonalcoholic fatty liver disease (NAFLD) in adult offspring has not been explored. Likewise, the molecular mechanisms associated with AME-induced NAFLD have not been studied. The fatty acid translocase or cluster of differentiation 36 (CD36) has been implicated to play a causal role in the pathogenesis of WD-induced steatosis. However, it is unknown if CD36 plays a role in AME-induced NAFLD.ObjectiveThis study was designed to evaluate the isolated and additive impact of AME and postweaning WD on the expression and DNA methylation of hepatic Cd36 in association with the development of NAFLD in a novel mouse model.MethodsAME constituted maternal WD and maternal stress, whereas the control (Con) group had neither. Female C57BL/6J mice were fed a WD [40% fat energy, 29.1% sucrose energy, and 0.15% cholesterol (wt/wt)] 5 wk prior to pregnancy and throughout lactation. Non invasive variable stressors (random frequent cage changing, limited bedding, novel object, etc.) were applied to WD dams during the last third of pregnancy to produce an AME. Con dams consumed the control diet (CD) (10% fat energy, no sucrose or cholesterol) and were not exposed to stress. Male offspring were weaned onto either CD or WD, creating 4 experimental groups: Con-CD, Con-WD, AME-CD, and AME-WD, and evaluated for metabolic and molecular parameters at 120 d of age.ResultsAME and postweaning WD independently and additively increased the development of hepatic steatosis in adult male offspring. AME and WD independently and additively upregulated hepatic CD36 protein and mRNA expression and hypomethylated promoters 2 and 3 of the Cd36 gene.ConclusionsUsing a mouse AME model together with postweaning WD, this study demonstrates a role for CD36 in AME-induced NAFLD in offspring and reveals 2 regions of environmentally induced epigenetic heterogeneity within Cd36.

Project description:Cytosine methylation is an important DNA epigenetic modification. In vertebrates, methylation occurs at CpG sites, which are dinucleotides where a cytosine is immediately followed by a guanine in the DNA sequence from 5' to 3'. When located in the promoter region of a gene, DNA methylation is often associated with transcriptional silencing of the gene. Aberrant DNA methylation is associated with the development of various diseases such as cancer. Bisulfite sequencing (BS-seq) is the current "gold-standard" technology for high-resolution profiling of DNA methylation. Reduced representation bisulfite sequencing (RRBS) is an efficient form of BS-seq that targets CpG-rich DNA regions in order to save sequencing costs. A typical bioinformatics aim is to identify CpGs that are differentially methylated (DM) between experimental conditions. This workflow demonstrates that differential methylation analysis of RRBS data can be conducted using software and methodology originally developed for RNA-seq data. The RNA-seq pipeline is adapted to methylation by adding extra columns to the design matrix to account for read coverage at each CpG, after which the RRBS and RNA-seq pipelines are almost identical. This approach is statistically natural and gives analysts access to a rich collection of analysis tools including generalized linear models, gene set testing and pathway analysis. The article presents a complete start to finish case study analysis of RRBS profiles of different cell populations from the mouse mammary gland using the Bioconductor package edgeR. We show that lineage-committed cells are typically hyper-methylated compared to progenitor cells and this is true on all the autosomes but not the sex chromosomes. We demonstrate a strong negative correlation between methylation of promoter regions and gene expression as measured by RNA-seq for the same cell types, showing that methylation is a regulatory mechanism involved in epithelial linear commitment.

Dataset Information

Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment.

Publications

Differential gene body methylation and reduced expression of cell adhesion and neurotransmitter receptor genes in adverse maternal environment.

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