ACETYL-COA SYNTHETASE REGULATES HISTONE ACETYLATION AND HIPPOCAMPAL MEMORY

Metabolic production of acetyl-CoA is linked to histone acetylation and gene regulation, yet the precise mechanisms are largely unknown. Here we show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a direct regulator of histone acetylation in neurons and of spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in nuclei of differentiating neurons and localizes to upregulated neuronal genes near elevated histone acetylation. Reduction of ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of the cohort of neuronal genes. In adult mice, attenuation of hippocampal ACSS2 expression impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a unique connection between cellular metabolism, gene regulation, and neural plasticity, establishing a link between acetyl-CoA generation “on-site” at chromatin for histone acetylation and the transcription of critical neuronal genes.