ATP-Citrate Lyase Links Cellular Metabolism to Histone Acetylation

TLDR

In metazoans, histone acetylation depends on glucose‑derived acetyl‑CoA rather than acetate, because extracellular acetate is scarce. ACL converts glucose‑derived citrate to acetyl‑CoA, enabling growth‑factor‑induced and differentiation‑driven increases in histone acetylation and linking nutrient metabolism to gene expression.

Abstract

Histone acetylation in single-cell eukaryotes relies on acetyl coenzyme A (acetyl-CoA) synthetase enzymes that use acetate to produce acetyl-CoA. Metazoans, however, use glucose as their main carbon source and have exposure only to low concentrations of extracellular acetate. We have shown that histone acetylation in mammalian cells is dependent on adenosine triphosphate (ATP)-citrate lyase (ACL), the enzyme that converts glucose-derived citrate into acetyl-CoA. We found that ACL is required for increases in histone acetylation in response to growth factor stimulation and during differentiation, and that glucose availability can affect histone acetylation in an ACL-dependent manner. Together, these findings suggest that ACL activity is required to link growth factor-induced increases in nutrient metabolism to the regulation of histone acetylation and gene expression.