Ethanol-related alterations in gene expression patterns in the developing murine hippocampus

Mandal, Chanc hal; Park, Kyoung Sun; Jung, Kyoung Hwa; Chai, Young Gyu

doi:10.1093/abbs/gmv050

Cited by 22 publications

(26 citation statements)

References 47 publications

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“…In an ethanol exposure paradigm similar to the one used in this study in which rats were exposed to intermittent ethanol and their prefrontal cortex was analyzed 21 days after the last exposure, ion channels, including those that influence neurotransmitter release through effects on membrane potentials and calcium flux, emerged as one of the top GO categories in a miRNA and a DNA methylation study (Tapocik et al, 2013; Barbier et al, 2015). Calcium signaling also emerged as an important pathway following maternal binge-like ethanol doses in embryonic day 18 fetuses in a microarray study (Mandal et al, 2015b). Our results therefore further indicate an important role for calcium signaling in AUD, and suggest epigenetic mechanisms may encode persisting alterations in this pathway.…”

Section: Discussionmentioning

confidence: 99%

Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure

et al. 2018

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Alcohol use disorder (AUD) is a chronic mental illness in which patients often achieve protracted periods of abstinence prior to relapse. Epigenetic mechanisms may provide an explanation for the persisting gene expression changes that can be observed even after long periods of abstinence and may contribute to relapse. In this study, we examined two histone modifications, histone 3 lysine 4 tri-methylation (H3K4me3) and histone 3 lysine 27 tri-methylation (H3K27me3), in the prefrontal cortex of Withdrawal Seizure Resistant (WSR) mice 21 days after 72 h of ethanol vapor exposure. These histone modifications were selected because they are associated with active promoters (H3K4me3) and repressed gene expression in a euchromatic environment (H3K27me3). We performed a genome-wide analysis to identify differences in H3K4me3 and H3K27me3 levels in post-ethanol exposure vs. control mice by ChIP-seq. We detected a global reduction in H3K4me3 peaks and increase in H3K27me3 peaks in post-ethanol exposure mice compared to controls, these changes are consistent with persistent reductions in gene expression. Pathway analysis of genes displaying changes in H3K4me3 and H3K27me3 revealed enrichment for genes involved in proteoglycan and calcium signaling pathways, respectively. Microarray analysis of 7,683 genes and qPCR analysis identified eight genes displaying concordant regulation of gene expression and H3K4me3/H3K27me3. We also compared changes in H3K4me3 and/or H3K27me3 from our study with changes in gene expression in response to ethanol from published literature and we found that the expression of 52% of the genes with altered H3K4me3 binding and 40% of genes with H3K27me3 differences are altered by ethanol exposure. The chromatin changes associated with the 21-day post-exposure period suggest that this period is a unique state in the addiction cycle that differs from ethanol intoxication and acute withdrawal. These results provide insights into the enduring effects of ethanol on proteoglycan and calcium signaling genes in the brain.

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Section: Discussionmentioning

confidence: 99%

Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure

et al. 2018

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“…When the control group brain size was normalized to a value of 100, the relative values in the ethanol-treated group for diameters a and b were 92.44 and 94.36, respectively. This result clearly indicates that a binge level of ethanol treatment during the synaptogenesis period evoked smaller brain volume, as did ethanol treatment during neurogenesis (Mandal et al, 2015).…”

Section: Resultsmentioning

confidence: 72%

Effects of postnatal alcohol exposure on hippocampal gene expression and learning in adult mice

et al. 2015

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Fetal alcohol syndrome (FAS) is a condition resulting from excessive drinking by pregnant women. Symptoms of FAS include abnormal facial features, stunted growth, intellectual deficits and attentional dysfunction. Many studies have investigated FAS, but its underlying mechanisms remain unknown. This study evaluated the relationship between alcohol exposure during the synaptogenesis period in postnatal mice and subsequent cognitive function in adult mice. We delivered two injections, separated by 2 h, of ethanol (3 g/kg, ethanol/saline, 20% v/v) to ICR mice on postnatal day 7. After 10 weeks, we conducted a behavioral test, sacrificed the animals, harvested brain tissue and analyzed hippocampal gene expression using a microarray. In ethanol-treated mice, there was a reduction in brain size and decreased neuronal cell number in the cortex, and also cognitive impairment. cDNA microarray results indicated that 1,548 genes showed a > 2-fold decrease in expression relative to control, whereas 974 genes showed a > 2-fold increase in expression relative to control. Many of these genes were related to signal transduction, synaptogenesis and cell membrane formation, which are highlighted in our findings.

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“…Mouse and rat studies showed the association between prenatal ethanol exposure and gene expression changes in postnatal and adult stages [34][35][36][37] . This study examined ethanol-induced gene expression changes during embryogenesis before gastrulation.…”

Section: Discussionmentioning

confidence: 99%

Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects

Sarmah

Srivastava

McClintick

et al. 2020

Sci Rep

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Ethanol exposure during prenatal development causes fetal alcohol spectrum disorder (FASD), the most frequent preventable birth defect and neurodevelopmental disability syndrome. The molecular targets of ethanol toxicity during development are poorly understood. Developmental stages surrounding gastrulation are very sensitive to ethanol exposure. To understand the effects of ethanol on early transcripts during embryogenesis, we treated zebrafish embryos with ethanol during pre-gastrulation period and examined the transcripts by Affymetrix GeneChip microarray before gastrulation. We identified 521 significantly dysregulated genes, including 61 transcription factors in ethanol-exposed embryos. Sox2, the key regulator of pluripotency and early development was significantly reduced. Functional annotation analysis showed enrichment in transcription regulation, embryonic axes patterning, and signaling pathways, including Wnt, Notch and retinoic acid. We identified all potential genomic targets of 25 dysregulated transcription factors and compared their interactions with the ethanol-dysregulated genes. This analysis predicted that Sox2 targeted a large number of ethanoldysregulated genes. A gene regulatory network analysis showed that many of the dysregulated genes are targeted by multiple transcription factors. Injection of sox2 mRNA partially rescued ethanol-induced gene expression, epiboly and gastrulation defects. Additional studies of this ethanol dysregulated network may identify therapeutic targets that coordinately regulate early development.Fetal alcohol spectrum disorder (FASD) is caused by the exposure to ethanol during prenatal developmental 1-3 . FASD patients display a range of morphological deformities and neurological deficits, including characteristic craniofacial dysmorphology, cognitive impairment, sensory defects, motor disabilities and organ deformities. A recent meta-analysis of FASD among children and youth showed the prevalence is approximately 0.8% globally, but it exceeds 1% in 76 countries 4 . The World Health Organization (WHO) European Region has the highest prevalence of FASD (1.98%) followed by the WHO Region of Americas (0.88%) 4 . Among all the countries studied to date, FASD is the most prevalent in South Africa where the prevalence is as high as 11.1% 4 . FASD prevalence is notably higher among special populations, for example, low socioeconomic status populations 5,6 , children in orphanages, people in psychiatric care etc. 4 .Despite various proposed mechanisms to explain FASD etiology, the molecular targets of ethanol toxicity during development are poorly understood. Conception through gastrulation are sensitive periods for ethanol-induced defects 7,8 . During this period stem and progenitor cells transition from pluripotency to one of the three germ layers, and the cells undergo coordinated movements to organize the body plan 9,10 . These effects are regulated transcriptionally, for example, through the maternal to zygotic transition and the pluripotency transcriptional circuit. S...

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Ethanol-related alterations in gene expression patterns in the developing murine hippocampus

Cited by 22 publications

References 47 publications

Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure

Stable Histone Methylation Changes at Proteoglycan Network Genes Following Ethanol Exposure

Effects of postnatal alcohol exposure on hippocampal gene expression and learning in adult mice

Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects

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