Alteration of Gene Expression, DNA Methylation, and Histone Methylation in Free Radical Scavenging Networks in Adult Mouse Hippocampus following Fetal Alcohol Exposure

Abstract

The molecular basis of Fetal Alcohol Spectrum Disorders (FASD) is poorly understood; however, epigenetic and gene expression changes have been implicated. We have developed a mouse model of FASD characterized by learning and memory impairment and persistent gene expression changes. Epigenetic marks may maintain expression changes over a mouse’s lifetime, an area few have explored. Here, mice were injected with saline or ethanol on postnatal days four and seven. At 70 days of age gene expression microarray, methylated DNA immunoprecipitation microarray, H3K4me3 and H3K27me3 chromatin immunoprecipitation microarray were performed. Following extensive pathway analysis of the affected genes, we identified the top affected gene expression pathway as “Free radical scavenging”. We confirmed six of these changes by droplet digital PCR including the caspase Casp3 and Wnt transcription factor Tcf7l2. The top pathway for all methylation-affected genes was “Peroxisome biogenesis”; we confirmed differential DNA methylation in the Acca1 thiolase promoter. Altered methylation and gene expression in oxidative stress pathways in the adult hippocampus suggests a novel interface between epigenetic and oxidative stress mechanisms in FASD.

Chromatin Switches during Neural Cell Differentiation and Their Dysregulation by Prenatal Alcohol Exposure

“…Of the 11 genes displaying changes in H3K4me3, five followed the pattern of expression generally associated with this histone modification (i.e., increased H3K4me3 associated with increased expression, or decreased H3K4me3 associated with decreased expression), while the other six did not. All four genes with changes in H3K27me3 displayed decreased H3K27me3 and increased gene expression [166]. This study supports the notion that one or even a few marks in the histone tails do not always determine whether a gene is expressed or not.…”

Global DNA Methylation and Histone Posttranslational Modifications in Human and Nonhuman Primate Brain in Association with Prenatal Alcohol Exposure

“…Because rodent brains are relatively immature at birth, many experiments use early postnatal alcohol administration to model late gestation human in utero exposure. Hippocampal and neocortical tissue from mice and rats that received alcohol during postnatal days 1 to 11 had increases in global DNA methylation, H3K4me3, H3K9me2, H3K27me2, and H3K27me3 (Chater‐Diehl et al., ; Otero et al., ; Subbanna et al., , ) and decreases in H3K9me2 and H3K27me2 (Subbanna et al., ). These results do not coincide with our findings.…”

p53‐Mediated Activities in NS‐5 Neural Stem Cells: Effects of Ethanol

“…Following DNA damage, p53 activation induces the transcription of genes related to cell cycle restriction, DNA repair, and cell death (Lane, ; Levine et al., ). EtOH causes oxidative DNA damage and thereby upsets the balance between the proliferation and death of NSCs (Camarillo and Miranda, ; Chater‐Diehl et al., ; Henderson et al., ; Hicks and Miller, , ; Hicks et al., ). EtOH also alters the expression of p53 (Kuhn and Miller, ) and the incidence of p53‐mediated cell proliferation and death (Miller et al., ).…”

“…One prevalent toxin that induces oxidative stress (Henderson et al., ; Hicks et al., ) and produces DNA damage (e.g., Brooks, ; Hicks and Miller, ; LaMarche et al., ) is ethanol (EtOH). Such damage is affected by changes in the transcriptome (Berres et al., ; Kleiber et al., ), transcript methylation (Chater‐Diehl et al., ; Hicks et al., ; Liu et al., ), and protein expression (Mason et al., ).…”