Dynamic interplay between cellular metabolism and histone acetylation is a key mechanism underlying metabolic control of epigenetics. In particular, the central metabolite acetyl-coenzyme A (acetyl-CoA) acts as the acetyl-donor for histone acetylation in both an enzymatic and non-enzymatic manner. Since members of the family of histone acetyl transferases (HATs) that catalyze the acetylation of histone tails possess a Michaelis constant (Km) within the range of physiological cellular acetyl-CoA concentrations, changing concentrations of acetyl-CoA can restrict or promote enzymatic histone acetylation. Likewise, non-enzymatic histone acetylation occurs at physiological concentrations. These concepts implicate acetyl-CoA as a rheostat for nutrient availability acting, in part, by controlling histone acetylation. Histone acetylation is an important epigenetic modification that controls gene expression and acetyl-CoA dependent changes in both histone acetylation and gene expression have been shown in yeast and mammalian systems. However, quantifying the metabolic conditions required to achieve specific changes in histone acetylation is a major challenge. The relationship between acetyl-CoA and histone acetylation may be influenced by a variety of factors including sub-cellular location of metabolites and enzymes, relative quantities of metabolites, and substrate availability/preference. A diversity of substrates can contribute the two-carbon acyl-chain to acetyl-CoA, a number of pathways can create or degrade acetyl-CoA, and only a handful of potential mechanisms for the crosstalk between metabolism and histone acetylation have been explored. The centrality of acetyl-CoA in intermediary metabolism means that acetyl-CoA levels may change, or be resistant to change, in unexpected ways. Thus, quantification of relevant metabolites is critical evidence in understanding how the nutrient rheostat is set in normal and pathological contexts. Coupling metabolite quantitation with isotope tracing to examine fate of specific metabolites is critical to the crosstalk between metabolism and histone acetylation, including but not limited to acetyl-CoA provides necessary context. This chapter provides guidance on experimental design of quantification with isotope dilution and/or tracing of acetyl-CoA within a targeted or highly multiplexed multi-analyte workflow.

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Journal Article

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Trefely S, Doan MT, Snyder NW

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