Local acetyl-CoA metabolism and acetate recycling as epigenetic regulators of chromatin dynamics.

Histone acetylation depends on acetyl-CoA, a central metabolic intermediate linking nutrient availability to chromatin regulation. Beyond bulk acetyl-CoA abundance, accumulating evidence indicates that chromatin-proximal acetyl-CoA production and acetate recycling provide spatial control over histone acetylation. In budding yeast, acetyl-CoA synthetase Acs2 supports nucleocytosolic acetyl-CoA production and associates with chromatin during transcriptional transitions, enabling local acetyl-CoA generation for histone acetyltransferases. Its mammalian ortholog, ACSS2, can accumulate in the nucleus in response to metabolic or signaling cues, where it recaptures acetate released by histone deacetylation to sustain promoter-localized histone acetylation. Acs2/ACSS2 also function within multi-enzyme or chromatin-associated assemblies, such as the yeast SESAME complex, coupling acetate metabolism with other metabolic and epigenetic pathways. These mechanisms influence gene expression, heterochromatin maintenance, senescence, and tumor-associated transcriptional programs. Together, these findings support a spatial model in which local metabolite production shapes epigenetic output independently of bulk metabolite abundance. Defining how such nuclear metabolic microenvironments are established and regulated may refine our understanding of metabolic control of chromatin and inform more selective therapeutic strategies.