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Hippocampal transcriptome analysis following maternal separation in a mouse model of fetal alcohol spectrum disorder

ABSTRACT: Fetal alcohol spectrum disorders (FASD) are common, seen in 1-5% of the population in the United States and Canada. Regrettably, children diagnosed with FASD are not likely to remain with their biological parents, facing early maternal separation and foster placements throughout childhood. We have modeled FASD in mice via prenatal alcohol exposure and further induce early life stress through maternal separation. We report an association between adult hippocampal gene expression and prenatal and postnatal treatment that is related to behavioral changes. Clustering of expression profiles through weighted gene co-expression network analysis (WGCNA) identifies a set of transcripts associated with anxiety-like behavior as well as treatment group. Genes in this module are overrepresented by genes involved in transcriptional regulation and other pathways related to neurodevelopment. Interestingly, one member of this module, Polr2a, polymerase (RNA) II (DNA directed) polypeptide A, is downregulated by the combination of prenatal ethanol and postnatal stress in an RNA-Seq experiment and qPCR validation. Together, transcriptional control is implicated as a potential underlying mechanism leading to anxiety-like behavior via environmental insults. Greater understanding of the role of prenatal alcohol exposure and postnatal stress in altering the hippocampal transcriptome in the hippocampus is warranted. Further research is required to elucidate the mechanism involved and use this insight towards early diagnosis and amelioration strategies involving children born with FASD.

ORGANISM(S): Mus musculus

PROVIDER: GSE133369 | GEO | 2019/06/27

REPOSITORIES: GEO

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Project description:Fetal alcohol spectrum disorder (FASD) is a common developmental behavioral disorder caused by maternal drinking during pregnancy. Children born with FASD often face additional stress, particularly maternal separation that adds yet additional deficits. The mechanism associated with this phenomenon is not known. Using a mouse model, prenatal ethanol exposure and maternal separation stress have resulted in behavioral deficits and the combination of treatments results in more than additive effects. In addition, behavioral alterations are associated with changes in hippocampal gene expression that persist into adulthood. What initiates and maintains these changes remains to be established and forms the focus of this research. Specifically, MeDIP-Seq was used to assess how changes in promoter DNA methylation are affected by the combination of prenatal ethanol exposure and maternal separation stress with the potential to affect gene expression. The novel results show different sets of genes implicated by promoter DNA methylation affected by both treatments independently, and a relatively unique set of genes affected by the combination of treatments. Prenatal ethanol exposure leads to altered promoter DNA methylation at genes important for brain function and transcriptional regulation. Maternal separation stress leads to changes at genes important for histone methylation and immune response, and the combination of two treatments results in DNA methylation changes at genes important for neuronal migration and immune response. Our dual results on gene expression and DNA methylation from the same samples have allowed comparison of the two observations. There is minimal reciprocal overlap between changes in promoter DNA methylation and gene expression, although overlapping genes tend to be critical for brain development and function. These results suggest that epigenetic mechanisms beyond promoter DNA methylation must be involved in lasting gene expression alterations leading to behavioral deficits implicated in FASD.

Project description:Background: Fetal alcohol spectrum disorder (FASD) is a developmental disorder that manifests through a range of cognitive, adaptive, physiological, and neurobiological deficits resulting from prenatal alcohol exposure. Although the North American prevalence is currently estimated at 2-5%, FASD has proven difficult to identify in the absence of the overt physical features characteristic of fetal alcohol syndrome. As interventions may have the greatest impact at an early age, accurate biomarkers are needed to identify children at risk for FASD. Building on our previous work identifying distinct DNA methylation patterns in children and adolescents with FASD, we have attempted to validate these associations in a different clinical cohort and to use our DNA methylation signature to develop a possible epigenetic predictor of FASD. Methods: Genome-wide DNA methylation patterns were analyzed using the Illumina HumanMethylation450 array in the buccal epithelial cells of a cohort of 48 individuals aged 3.5-18 (24 FASD cases, 24 controls). The DNA methylation predictor of FASD was built using a stochastic gradient boosting model on our previously published dataset FASD cases and controls (GSE80261). The predictor was tested on the current dataset and an independent dataset of 48 autism spectrum disorder cases and 48 controls (GSE50759). Results: We validated findings from our previous study that identified a DNA methylation signature of FASD, replicating the altered DNA methylation levels of 161/648 CpGs in this independent cohort, which may represent a robust signature of FASD in the epigenome. We also generated a predictive model of FASD using machine learning in a subset of our previously published cohort of 179 samples (83 FASD cases, 96 controls), which was tested in this novel cohort of 48 samples and resulted in a moderately accurate predictor of FASD status. Upon testing the algorithm in an independent cohort of individuals with autism spectrum disorder, we did not detect any bias towards autism, sex, age, or ethnicity. Conclusion: These findings further support the association of FASD with distinct DNA methylation patterns, while providing a possible entry point towards the development of epigenetic biomarkers of FASD.

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Hippocampal transcriptome analysis following maternal separation in a mouse model of fetal alcohol spectrum disorder

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