A compelling body of evidence suggests an intimate relationship between metabolic state and chromatin regulation. This link is manifested in key metabolites that participate in biochemical pathways as intermediates, and function as cofactors to regulate chromatin modifying enzymes. Of particular interest is the metabolite acetyl-CoA, given its central role as an intermediate of cellular energy metabolism and key determinant of all histone acetylation. How nuclear acetyl-CoA levels are regulated to, in turn, control histone acetylation is under intense investigation, and holds promise for increased understanding of the molecular mechanisms adapting gene expression to internal and external stimuli. We studied the relationship between histone modification dynamics and the dramatic transcriptional changes that occur during nutrient‐induced cell cycle re-entry from quiescence in the yeast S. cerevisiae. ChIP‐seq and SILAC-based mass spec revealed genome‐wide shifts in histone acetylation at growth and stress genes as cells exit quiescence and transcription dramatically changes. Strikingly, however, the patterns of histone methylation remain intact. We conclude that histone acetylation, in contrast to methylation, rapidly responds to metabolic state, driving growth gene transcription in nutrient-induced cell cycle re-entry. Next, we set out to investigate how nuclear acetyl-CoA is regulated to control histone acetylation in mammalian cells. We reveal a previously unknown function of the central metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) as a chromatin-bound transcriptional coactivator that stimulates histone acetylation and gene expression. We show that ACSS2 is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. Our data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA, to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These findings reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation.