Epigenetic and transcriptomic impacts of ethanol vary by brain region and extent of exposure

Epigenetic and transcriptional mechanisms are key contributors to alcohol use disorder (AUD). However, a better understanding of the specific genes, transcripts, and chromatin marks affected is necessary to inform novel pharmacotherapies. Here, we systematically investigate the genome-wide epigenetic and transcriptomic effects of ethanol across key brain regions relevant to AUD and assess how these outcomes differ between acute and chronic exposure in male C57BL/6J mice. We show that alcohol-derived acetate contributes to histone acetylation in the brain in response to acute or chronic exposure, with a broader and more robust effect following repeated exposure. Further, we find that chromatin and transcriptomic changes elicited by acute or chronic ethanol exposure are predominantly specific to brain region, and observe more robust dysregulation of gene and transcript expression following acute exposure. We show that ethanol-induced transcriptional changes are paradigm-dependent in some brain regions, most strikingly in the ventral hippocampus. Overall, our results systematically illuminate and compare key epigenetic and transcriptomic outcomes linked to acute and chronic ethanol exposure, which will guide the development of future therapeutic interventions. Significance Statement This is the first study to systematically investigate epigenetic and transcriptomic changes following acute or chronic exposure to alcohol, focusing on key regions previously linked to substance use disorders. We show the molecular impact of alcohol varies among brain regions and in part depends on the extent of alcohol exposure. Our results provide unprecedented detail on how alcohol affects transcriptional regulation in the brain, which in turn will inform the development of needed novel therapeutic interventions for alcohol use disorder.