Alcohol metabolism directly fuels histone acetylation in the brain [RNA-Seq II]

In the adult brain, epigenetic control of gene expression has important roles in the processing of neural activity. Emerging evidence suggests that epigenetic regulation is dependent on metabolic state, implicating specific metabolic factors in neural functions that drive behavior. In neurons, histone acetylation is dependent on the metabolite acetyl-CoA that is produced from acetate by chromatin-bound ACSS21. Here, using in vivo stable isotope labeling in mouse, we show that alcohol metabolism rapidly fuels histone acetylation in the brain 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. Injection of labeled alcohol into a pregnant mouse results in incorporation of labeled acetyl groups into gestating fetal brains, indicating that the acetate passes through the placenta. In isolated primary hippocampal neurons ex vivo, extracellular acetate induced learning and memory-related transcriptional programs that were sensitive to ACSS2 inhibition. Strikingly, alcohol-related associative learning requires ACSS2 in vivo. These findings establish a novel and direct link between alcohol metabolism and neuronal ACSS2-dependent histone acetylation in the brain, providing evidence that dynamic acetate release from liver metabolism may travel to the brain for direct epigenetic regulation in neurons. This experiment assesses the gene expression response to EtOH in mouse hippocampus by RNA-seq, in the presence or absence of enzyme ACSS2. EtOH was injected systemically via intraperitoneal injection, as was an ACSS2 shRNA knockdown. Controls for EtOH treatment (two replicates each of ACSS2- or control) were previously published under GEO series GSE90855 and are re-uploaded here. Three and four replicates (dorsal and ventral) of EtOH treated ACSS2+ samples are included here, as are five and four replicates (dorsal and ventral) of EtOH treated ACSS2- samples. An additional total hippocampus ACSS2- EtOH+ sample is also included.