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Biochem Biophys Res Commun. 2006 Sep 22;348(2):351-8. Epub 2006 Jul 13.

Dynamic changes in chromatin acetylation and the expression of histone acetyltransferases and histone deacetylases regulate the SM22alpha transcription in response to Smad3-mediated TGFbeta1 signaling.

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  • 1Department of Internal Medicine, Wayne State University, Detroit, MI 48201, USA.

Abstract

TGFbeta1 plays critical roles in stimulating smooth muscle gene transcription during myofibroblast and smooth muscle cell (SMC) differentiation. Increasing evidence demonstrates that histone 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 TGFbeta1-induced SM22 promoter activities. We found that overexpressing HAT proteins such as p300 and CBP enhances TGFbeta1-induced SM22 promoter activities; conversely, overexpressing HAT inhibitor such as Twist1 (but not Twist2/Dermo-1) and E1A suppresses this effect of TGFbeta1. We also found that TSA, a HDAC inhibitor that stimulates histone acetylation of the SM22alpha 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. TGFbeta1 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 TGFbeta1-induced as well as Smad3 and myocardin-activated SM22 promoter. Moreover, chromatin immunoprecipitation (ChIP) assays show that TGFbeta1 induces histone acetylation at the SM22alpha locus. This study demonstrates that the balance of HAT and HDAC expression affects TGFbeta1-induced SM22alpha transcription; TGFbeta1-induced SM22alpha transcription is accompanied by histone hyperacetylation at the SM22alpha locus. This study provides the first evidence showing that histone hyperacetylation of the SM22 promoter is a target of TGFbeta1 signaling, suggesting that modulation of histone acetylation is involved in the molecular mechanisms of TGFbeta1-regulated SMC gene transcription.

PMID:
16876108
[PubMed - indexed for MEDLINE]
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