ALCOHOL METABOLISM CONTRIBUTES TO BRAIN HISTONE ACETYLATION

Abstract

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.