ATP-citrate lyase regulates chromatin-dependent activation and maintenance of the myofibroblast gene program and cardiac fibrosis

Differentiation of cardiac fibroblasts (CFs) to myofibroblasts is necessary for matrix remodeling and fibrosis in heart failure. We previously reported mitochondrial calcium signaling drives a-ketoglutarate-dependent histone demethylation, promoting the myofibroblast gene program. Here, we investigated the role of ATP-citrate lyase (ACLY), a key enzyme for acetyl-CoA biosynthesis, in histone acetylation regulating myofibroblast formation and persistence in cardiac fibrosis. Inactivation of ACLY prevented, and importantly reversed, myofibroblasts towards quiescence. Genetic deletion of Acly in activated myofibroblasts prevented fibrosis and preserved cardiac function in murine pressure-overload. TGFß stimulation enhanced ACLY nuclear localization and increased H3K27ac at fibrotic gene loci. Pharmacological inhibition of ACLY or forced nuclear expression of dominant-negative ACLY mutant prevented myofibroblast formation and H3K27ac. Our data indicate nuclear ACLY activity is necessary for myofibroblast differentiation and persistence by maintaining histone acetylation at TGFß-induced myofibroblast genes. These findings provide novel clinical rational to prevent and reverse pathological fibrosis. CUT&RUN Sequencing for H3K27ac on the role of ACLY in myofibroblast differentiaton. Overall design: H3K27ac-enriched DNA using CUT&RUN from cardiac fiborblasts stimulated with or without TGFß and treated with and without ACLY inhibitor.