ALCOHOL METABOLISM CONTRIBUTES TO BRAIN HISTONE ACETYLATION

Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, implicating specific metabolic factors in neural functions that drive behavior(1). In neurons, histone acetylation relies on the metabolite acetyl-CoA that is produced from acetate by chromatin-bound acetyl-CoA synthetase 2 (ACSS2)(2). Notably, a major source of acetate is via breakdown of alcohol in the liver, leading to rapidly increasing blood acetate(3). Neuronal histone acetylation may thus be under the influence of alcohol-derived acetate(4), with potential effects on alcohol-induced brain gene expression and behavior(5). Here, using in vivo stable isotope labeling in mouse, we show that alcohol metabolism contributes to rapid histone acetylation in the brain in part by direct deposition of alcohol-derived acetyl groups onto histones in an ACSS2-dependent manner. A similar induction was observed with heavy labeled acetate injection in vivo. In a pregnant mouse, exposure to labeled alcohol resulted in incorporation of labeled acetyl groups into gestating fetal brains. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced learning and memory-related transcriptional programs that were sensitive to ACSS2 inhibition. Notably, we showed that alcohol-related associative learning requires ACSS2 in vivo. These findings support a direct link between alcohol metabolism and gene regulation through ACSS2-dependent histone acetylation in the brain.