Recent evidence suggests that epigenetic regulation is dependent on metabolic state and implicates specific metabolic factors in neuronal functions that control behavior. In neurons, acetylation of histones relies on the metabolite acetyl-CoA, which is produced from acetate by chromatin-bound acetyl-CoA synthetase 2 (ACSS2)2.
Of note, degradation of alcohol in the liver leads to a rapid increase in blood acetate levels, making alcohol a major source of acetate in the body. Histone acetylation in neurons may therefore be under the influence of alcohol-derived acetate, with potential implications for alcohol-induced brain gene expression and behavior.
Here, using in vivo stable isotope labeling in mice, we show that alcohol metabolism contributes to the rapid acetylation of histones in the brain, and that this occurs in part through the direct deposition of alcohol-derived acetyl groups onto histones in an ACSS2-dependent manner.
Similar direct deposition was observed in mice injected with heavily labeled acetate in vivo. In a pregnant mouse, exposure to labeled alcohol resulted in incorporation of labeled acetyl groups into the brain of the pregnant fetus.
In isolated primary hippocampal neurons, extracellular acetate induced ex vivo transcriptional programs related to learning and memory that were sensitive to ACSS2 inhibition.
We show that alcohol-induced associative learning requires ACSS2 in vivo. These results suggest that there is a direct link between alcohol metabolism and gene regulation through ACSS2-dependent acetylation of histones in the brain.