Microglia isolated from juvenile offspring of dams with allergic asthma exhibit methylation and transcriptional alterations to autism risk genes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE94569 | GEO | 2017/12/20
SECONDARY ACCESSION(S): PRJNA371477
REPOSITORIES: GEO
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Project description:Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. Dysregulation in immune responses during pregnancy, such as those that develop with chronic allergic asthma, increase the risk of a having a child with an Autism Spectrum Disorder (ASD). We recently developed a mouse model of maternal allergic asthma (MAA) that induces alterations in behavioral outcomes of the offspring including changes in sociability, repetitive and perseverative behaviors. Pregnancy is also a time when epigenetic changes help a static genome adapt to the maternal environment, and consequently activation of the maternal immune system may alter the regulation of gene expression in the developing fetal brain. Perinatal exposure to maternal asthma alters DNA methylation of immune-related genes in human infants, suggesting that maternal asthma has long-lasting effects on the offspring’s’ immune function. Here we used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation combined with RNA sequencing to examine gene expression in acutely isolated microglia from juvenile MAA offspring. Differential analysis revealed significant alterations in the epigenome of microglia from MAA compared to PBS treated control offspring and identified genes involved in controlling microglial sensitivity to the environment and shaping both synaptic and long-range neuronal connections in the developing brain. Genes with altered methylation and expression in MAA juvenile microglia significantly overlapped with those identified in adult cortex from offspring of a different maternal immune activation (polyIC) autism model and with a curated list of autism risk genes in human, supporting a role for microglia in the pathogenesis of ASD.
2017-12-20 | GSE94568 | GEO
Project description:Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. Dysregulation in immune responses during pregnancy, such as those that develop with chronic allergic asthma, increase the risk of a having a child with an Autism Spectrum Disorder (ASD). We recently developed a mouse model of maternal allergic asthma (MAA) that induces alterations in behavioral outcomes of the offspring including changes in sociability, repetitive and perseverative behaviors. Pregnancy is also a time when epigenetic changes help a static genome adapt to the maternal environment, and consequently activation of the maternal immune system may alter the regulation of gene expression in the developing fetal brain. Perinatal exposure to maternal asthma alters DNA methylation of immune-related genes in human infants, suggesting that maternal asthma has long-lasting effects on the offspring’s’ immune function. Here we used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation combined with RNA sequencing to examine gene expression in acutely isolated microglia from juvenile MAA offspring. Differential analysis revealed significant alterations in the epigenome of microglia from MAA compared to PBS treated control offspring and identified genes involved in controlling microglial sensitivity to the environment and shaping both synaptic and long-range neuronal connections in the developing brain. Genes with altered methylation and expression in MAA juvenile microglia significantly overlapped with those identified in adult cortex from offspring of a different maternal immune activation (polyIC) autism model and with a curated list of autism risk genes in human, supporting a role for microglia in the pathogenesis of ASD.
2017-12-20 | GSE94525 | GEO
Project description:Dysregulation in immune responses during pregnancy increases the risk of a having a child with an autism spectrum disorder (ASD). Asthma is one of the most common chronic diseases among pregnant women, and symptoms often worsen during pregnancy. We recently developed a mouse model of maternal allergic asthma (MAA) that induces changes in sociability, repetitive, and perseverative behaviors in the offspring. Since epigenetic changes help a static genome adapt to the maternal environment, activation of the immune system may epigenetically alter fetal microglia, the brain's resident immune cells. We therefore tested the hypothesis that epigenomic alterations to microglia may be involved in behavioral abnormalities observed in MAA offspring. We used the genome-wide approaches of whole genome bisulfite sequencing to examine DNA methylation and RNA sequencing to examine gene expression in microglia from juvenile MAA offspring. Differentially methylated regions were enriched for immune signaling pathways and important microglial developmental transcription factor binding motifs. Differential expression analysis identified genes involved in controlling microglial sensitivity to the environment and shaping neuronal connections in the developing brain. Differentially expressed genes significantly overlapped genes with altered expression in human ASD cortex, supporting a role for microglia in the pathogenesis of ASD.
| S-EPMC5767155 | biostudies-literature
Project description:Microglia isolated from juvenile offspring of dams with allergic asthma exhibit methylation and transcriptional alterations to autism risk genes
| PRJNA371477 | ENA
Project description:Offspring of obese mothers suffer higher risks of type 2 diabetes due to increased adiposity and decreased β cell function. To date, the sex-differences in offspring islet insulin secretion during early life has not been evaluated extensively, particularly prior to weaning at postnatal day 21 (P21). To determine the role of maternal obesity on offspring islet insulin secretion, C57BL/6J female dams were fed chow or western diet from 4 weeks prior to mating to induce maternal obesity. First, offspring of chow-fed and obese dams were evaluated on postnatal day 21 (P21) prior to weaning for body composition, glucose and insulin tolerance, and islet phasic insulin-secretion. Compared to same-sex controls, both male and female P21 offspring born to obese dams (MatOb) had higher body adiposity and exhibited sex-specific differences in glucose tolerance and insulin secretion. The male MatOb offspring developed the highest extent of glucose intolerance and lowest glucose-induced insulin secretion. In contrast, P21 female offspring of obese dams had unimpaired insulin secretion. Using SAX-HPLC, we found that male MatOb had a decrease in pancreatic heparan sulfate glycosaminoglycan, which is a macromolecule critical for islet health. Notably, 8-weeks-old offspring of obese dams continued to exhibit a similar pattern of sex-differences in glucose intolerance and decreased islet insulin secretion. Overall, our study suggests that maternal obesity induces sex-specific changes to pancreatic HSG in offspring and a lasting effect on offspring insulin secretion, leading to the sex-differences in glucose intolerance.
| S-EPMC8181410 | biostudies-literature
Project description:BackgroundAssociations between parental asthma and prenatal exposure to asthma medications with offspring autism spectrum disorder (ASD) have been reported. However, the associations might be confounded by unmeasured (genetic and shared environmental) familial factors.ObjectiveWe investigated the association between (a) maternal/paternal asthma and offspring ASD, and (b) prenatal exposures to ?2-agonists, other asthma medications and offspring ASD using cases and controls selected from the population as well as biological relatives with different degrees of relatedness.MethodsWe included all children (N = 1 579 263) born in Sweden 1992-2007. A nested case-control design was used to compare 22 894 ASD cases identified from the National Patient Register to (a) 228 940 age-, county- and sex-matched controls randomly selected from the population, (b) their eligible full-siblings (n = 1267), (c) half-siblings (n = 1323), (d) full-cousins (n = 11 477) and (e) half-cousins (n = 3337). Conditional logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for ASD in children differentially exposed to parental asthma or prenatal asthma medications.ResultsMaternal asthma was associated with increased risk of offspring ASD (OR 1.43, 95% CI 1.38-1.49); there was a weaker association for paternal asthma (OR 1.17, 95% CI 1.11-1.23). The risk of offspring ASD in mothers with asthma showed similar estimates when adjusting for shared familial factors among paternal half-siblings (OR 1.20, 95% CI 0.80-1.81), full-cousins (OR 1.28, 95% CI 1.16-1.41) and half-cousins (OR 1.30, 95% CI 1.10-1.54), albeit with wider confidence intervals. Prenatal exposure to asthma medications among subjects whose mothers had asthma was not associated with subsequent ASD.Conclusions and clinical relevanceIn this large observational study, parental asthma was associated with slightly elevated risk of ASD in offspring. More specifically, the increased risk by maternal asthma did not seem to be confounded by familial factors. There was no evidence of an association between asthma medications during pregnancy and offspring ASD.
| S-EPMC6849600 | biostudies-literature
Project description:We performed a pooled GWAS and individual genotyping in 269 children with allergic respiratory diseases comparing allergic children with and without asthma. We used a modular approach to identify the most significant loci associated with asthma by combining silhouette statistics and physical distance method with cluster-adapted thresholding. We found 97% concordance between pooled GWAS and individual genotyping, with 36 out of 37 top-scoring SNPs significant at individual genotyping level. The most significant SNP is located inside the coding sequence of C5, an already identified asthma susceptibility gene, while the other loci regulate functions that are relevant to bronchial physiopathology, as immune- or inflammation-mediated mechanisms and airway smooth muscle contraction. Integration with gene expression data (from mouse experimental asthma model taken from GSE6858 and GSE1301) showed that almost half of the putative susceptibility genes are differentially expressed in experimental asthma mouse models. Affymetrix SNP arrays (Mapping 250K NspI and StyI) were performed according to the manufacturer's directions on pooled DNA extracted from peripheral blood samples.The design is a pooled-GWAS. DNA samples were assigned to the Asthma group if displaying symptoms of asthma, alone or associated to other allergic phenotypes, including rhinoconjunctivitis (RC), and assigned to the RC group if displaying rhinitis or rhinoconjunctivits alone or associated to other allergic phenotypes, excluding asthma. Each of the two groups was subdiveded into 4 independent groups of samples, each containing 31-36 individuals. Individual DNA samples were then added to their respective pools in equivalent molar amounts. Each pool was labeled and hybridized independently on three different arrays (3 technical replicates for each pool).
2011-03-17 | E-GEOD-24481 | biostudies-arrayexpress
Project description: Not available
| S-EPMC7309532 | biostudies-literature
Project description:Accumulating evidence reveal that maternal smoking or perinatal nicotine replacement therapy impairs hippocampal neurogenesis, neural development, and cognitive behaviors in the offspring. Microglia is a source of non-neural regulation of neuronal development and postnatal neurogenesis. In this study, we explored the impact of nicotine on the microglia during the development of hippocampus. Developmental nicotine exposure in a mouse model was conducted by supplementing nicotine in the drinking water to mother mice during gestation and lactation period. We found that juvenile offspring with maternal nicotine exposure presented physical and neurobehavioral development delay and an increase in anxiety-like behavior in the open field test on postnatal day (PND) 20. To further detect possible developmental neurotoxic effects of nicotine in offspring and underlying mechanism, whole genome microarray analysis of the expression profile of the hippocampus was performed on postnatal day 20. Significant alterations in the expression of genes related to inflammatory, neurotransmitter, and synapsis were observed in the hippocampus after maternal nicotine exposure, as compared to the vehicle control. Concurrently, an increase in microglial markers and the presence of M2 polarity state in the hippocampus of the nicotine offspring were observed by histological analysis and confocal z-stacking scanning. The M2 microglial polarization state was further confirmed with in vitro primary microglia culture by cytokine array, and double-positive expression of BDNF/Iba1 in microglia by immunohistochemical staining in the juvenile offspring hippocampus was visualized. We also found that nicotine offspring showed an increase of neurite length in the molecular layer and CA1 by Tuj1 staining, as well as an increase in the expression of synapse associated protein, PSD95, but the expression of NeuroD1 in CA1 and CA3 reduced. In summary, maternal nicotine exposure dysregulates immune-related genes expression by skewing the polarity of M2 microglia in the hippocampus, which may cause abnormal cognitive and behavioral performance in the offspring.
| S-EPMC8144443 | biostudies-literature
Project description:Microglia are central nervous system (CNS) resident immune cells that have been implicated in neuroinflammatory pathogenesis of a variety of neurological conditions. Their manifold context-dependent contributions to neuroinflammation are only beginning to be elucidated, which can be attributed in part to the challenges of studying microglia in vivo and the lack of tractable in vitro systems to study microglia function. Organotypic brain slice cultures offer a tissue-relevant context that enables the study of CNS resident cells and the analysis of brain slice microglial phenotypes has provided important insights, in particular into neuroprotective functions. Here we use RNA sequencing, direct digital quantification of gene expression with nCounter® technology and targeted analysis of individual microglial signature genes, to characterize brain slice microglia relative to acutely-isolated counterparts and 2-dimensional (2D) primary microglia cultures, a widely used in vitro surrogate. Analysis using single cell and population-based methods found brain slice microglia exhibited better preservation of canonical microglia markers and overall gene expression with stronger fidelity to acutely-isolated adult microglia, relative to in vitro cells. We characterized the dynamic phenotypic changes of brain slice microglia over time, after plating in culture. Mechanical damage associated with slice preparation prompted an initial period of inflammation, which resolved over time. Based on flow cytometry and gene expression profiling we identified the 2-week timepoint as optimal for investigation of microglia responses to exogenously-applied stimuli as exemplified by treatment-induced neuroinflammatory changes observed in microglia following LPS, TNF and GM-CSF addition to the culture medium. Altogether these findings indicate that brain slice cultures provide an experimental system superior to in vitro culture of microglia as a surrogate to investigate microglia functions, and the impact of soluble factors and cellular context on their physiology.
| S-EPMC7812919 | biostudies-literature