Yin Yang 1 is increased in human heart failure and represses the activity of the human α-myosin heavy chain promoter

Yin Yang 1 (YY1) is a transcription factor that can repress or activate transcription of the genes with which it interacts. In this report we show that YY1 is a negative regulator of the alpha-myosin heavy chain (alphaMyHC) gene, which, with betaMyHC are the molecular motors of the heart. alphaMyHC mRNA and protein levels are down-regulated in hypertrophy and heart failure, and this is thought to be detrimental for cardiac contractility. We show that YY1 specifically interacts with the alphaMyHC promoter and that overexpression of YY1 in cardiac cells represses the activity of the alphaMyHC promoter. We also show that the 170-200-amino acid region of YY1, important for its interaction with histone acetyl transferases and histone deacetylases, is important for its repressive activity and that YY1 deleted in this region is an activator of the alphaMyHC promoter. Moreover, we show that YY1 levels and DNA binding activity are increased in failing human left ventricles and in a mouse model of hypertrophic cardiomyopathy, where alphaMyHC levels are decreased. These results suggest that YY1 is a negative regulator of alphaMyHC gene expression.