Acetyl-CoA production by Mediator-bound 2-ketoacid dehydrogenases boosts de novo histone acetylation and is regulated by nitric oxide

Histone-modifying enzymes depend on the availability of cofactors, with acetyl-coenzyme A (CoA) beingrequired for histone acetyltransferase (HAT) activity. The discovery that mitochondrial acyl-CoA-producingenzymes translocate to the nucleus suggests that high concentrations of locally synthesized metabolitesmay impact acylation of histones and other nuclear substrates, thereby controlling gene expression. Here,we show that 2-ketoacid dehydrogenases are stably associated with the Mediator complex, thus providinga local supply of acetyl-CoA and increasing the generation of hyper-acetylated histone tails. Nitric oxide (NO),which is produced in large amounts in lipopolysaccharide-stimulated macrophages, inhibited the activity ofMediator-associated 2-ketoacid dehydrogenases. Elevation of NO levels and the disruption of Mediatorcomplex integrity both affecteddenovohistone acetylation within a shared set of genomic regions. Our find-ings indicate that the local supply of acetyl-CoA generated by 2-ketoacid dehydrogenases bound to Mediatoris required to maximize acetylation of histone tails at sites of elevated HAT activity