TGF beta 1 plays critical roles in stimulating smooth muscle gene transcription during myofibroblast and smooth muscle cell (SMC) differentiation. Increasing evidence demonstrates that historic modification plays important roles in regulating gene transcription. Here, we investigated the effect of changes in the expression of histone acetyltransferases (HAT) or histone deacetylases (HDAC) on TGF beta 1-induced SM22 promoter activities. We found that overexpressing HAT proteins such as p300 and CBP enhances TGF beta 1-induced SM22 promoter activities; conversely, overexpressing HAT inhibitor such as Twist1 (but not Twist2/Dermo-1) and E1A suppresses this effect of TGF beta 1. We also found that TSA, a HDAC inhibitor that stimulates histone acetylation of the SM22 alpha locus, further enhances the transactivational activity of Smad2, Smad3 and Smad4, and relieves the inhibitory effect of Smad6, Smad7, and the dominant negative mutants of Smads. TGF beta 1 also stimulates the association of Smad3 (a potent transactivator for the SM22 promoter) and p300 by co-immunoprecipitation assay. In contrast, overexpressing HDAC 1-6 inhibits TGF beta 1-induced as well as Smad3 and myocardin-activated SM22 promoter. Moreover, chromatin immunoprecipitation (ChIP) assays show that TGF beta 1 induces histone acetylation at the SM22 alpha locus. This study demonstrates that the balance of HAT and HDAC expression affects TGF beta 1-induced SM22 alpha transcription; TGF beta 1-induced SM22 alpha transcription is accompanied by histone hyperacetylation at the SM22 alpha locus. This study provides the first evidence showing that historic hyperacetylation of the SM22 promoter is a target of TGF beta 1 signaling, suggesting that modulation of historic acetylation is involved in the molecular mechanisms of TGF beta 1-regulated SMC gene transcription. (c) 2006 Elsevier Inc. All rights reserved.