TGF-β1 modifies histone acetylation and acetyl-coenzyme A metabolism in renal myofibroblasts

Histone acetylation is an important modulator of gene expression in fibrosis. This study examined the effect of the pre-eminent fibrogenic cytokine transforming growth factor-beta 1 (TGF-(beta 1) on histone 3 (H3) acetylation and its regulatory kinetics in renal myofibroblasts. Fibroblasts propagated from rat kidneys after ureteric obstruction were treated with recombinant TGF-beta 1 or vehicle for 48 h. TGF-beta 1-induced myofibroblast activation was accompanied by a net decrease in total H3 acetylation, although changes in individual marks were variable. This was paralleled by a generalized reduction in histone acetyltransferases (HAT) and divergent changes in histone deacetylase (HDAC) enzymes at both transcript and protein levels. Globally, this was manifest in a reduction in total HAT activity and increase in HDAC activity. TGF-beta 1 induced a shift in cellular metabolism from oxidative respiration to aerobic glycolysis, resulting in reduced acetyl-CoA. The reduction in total H3 acetylation could be rescued by providing exogenous citrate or alternative sources of acetyl-CoA without ameliorating changes in HAT/HDAC activity. In conclusion, TGF-beta 1 produces a metabolic reprogramming in renal fibroblasts, with less H3 acetylation through reduced acetylation, increased deacetylation, and changes in carbon availability. Our results suggest that acetyl-CoA availability predominates over HAT and HDAC activity as a key determinant of H3 acetylation in response to TGF-beta 1.