Abstract
We have previously reported the deregulatory impact of ethanol on global DNA methylation of brain-derived neural stem cells (NSC). Here, we conducted a genome-wide RNA-seq analysis in differentiating NSC exposed to different modes of ethanol exposure. RNA-seq results showed distinct gene expression patterns and canonical pathways induced by ethanol exposure and withdrawal. Short-term ethanol exposure caused abnormal up-regulation of synaptic pathways, while continuous ethanol treatment profoundly affected brain cells’ morphology. Ethanol withdrawal restored the gene expression profile of differentiating NSC without rescuing impaired expression of epigenetics factors. Ingenuity Pathway Analysis (IPA) analysis predicated that ethanol may impact synaptic functions via GABA receptor signalling pathway and affects neural system and brain morphology. We identified Sptbn2, Dcc, and Scn3a as candidate genes which may link alcohol-induced neuronal morphology to brain structural abnormalities, predicted by IPA analysis. Cross-examination of Scn3a and As3mt in differentiated NSC from two different mouse strains (BL6 and CD1) showed a consistent pattern of induction and reduction, respectively. Collectively, our study identifies genetic networks, which may contribute to alcohol-mediated cellular and brain structural dysmorphology, contributing to our knowledge of alcohol-mediated damage to central nervous system, paving the path for better understanding of FASD pathobiology.
Highlights
Intensive efforts have focused on discovering FASD mechanism of disease to provide explanations on how alcohol affects fetal development
By examining RNA-seq reads mapped on gene transcripts with at least normalized 10 reads per gene, we found that 16675, 16550, and 15973 genes were expressed at D0, D2 and D8, respectively
By further clustering the differential gene expression results, we found that withdrawing ethanol (D8WE) restored the transcriptome as it clustered with D8Con, yet it is distinct from D8CE (Fig. 3B)
Summary
Intensive efforts have focused on discovering FASD mechanism of disease to provide explanations on how alcohol affects fetal development. Differentiating NSC are proven useful systems to study developmentally important genes, and for modeling therapy strategies of neurodevelopmental disorders[14,15,16,17,18,19] In this current study, we applied a genome-wide transcriptome analysis strategy to explore the genetic networks that are associated with altered gene expression program of brain-derived NSC under short-term and long-term ethanol exposure, compared to ethanol withdrawal. We applied a genome-wide transcriptome analysis strategy to explore the genetic networks that are associated with altered gene expression program of brain-derived NSC under short-term and long-term ethanol exposure, compared to ethanol withdrawal Alteration of these identified gene networks may contribute to abnormal brain morphology upon ethanol exposure
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