Here, we will concentrate on histone acetylation and metabolism. In one form of epigenetic regulation, histones can be acetylated at multiple positions on their N-terminal tail domains, affecting gene expression at the proximate genes. The extent of histone acetylation at specific sites depends on relative rates of deposition by histone acetyl transferases and removal by Histone Deacetylases (HDACs). The acetyl donor for histone acetylases is acetyl CoA, a metabolite that is produced downstream of glycolysis by the mitochondrial trichloroacetic acid cycle, by the β-oxidation of fatty acids, or by amino acid catabolism. Acetyl CoA is required for both fatty acid and cholesterol synthesis. ACLY generates acetyl CoA from citrate, ATP, and CoA (Figure 1). It partitions to both nucleus and cytoplasm, suggesting that nuclear acetyl CoA can be made locally (93) and that nucleocytoplasmic levels change with the metabolic status of cells, for example with glucose levels (94, 95). Knocking down ACLY reduces the acetylation of core histones H2B, H3, and H4 with consequent reductions in the expression proximate genes (93). As we have found ACLY to be transcriptionally regulated
