Yin Yang 1 Is Increased in Human Heart Failure and Represses the Activity of the Human α-Myosin Heavy Chain Promoter

Abstract

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 ␣-myosin heavy chain (␣MyHC) gene, which, with ␤MyHC are the molecular motors of the heart. ␣MyHC mRNA and protein levels are downregulated in hypertrophy and heart failure, and this is thought to be detrimental for cardiac contractility. We show that YY1 specifically interacts with the ␣MyHC promoter and that overexpression of YY1 in cardiac cells represses the activity of the ␣MyHC 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 ␣MyHC 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 ␣MyHC levels are decreased. These results suggest that YY1 is a negative regulator of ␣MyHC gene expression.

Single-stranded DNA-binding Proteins PURα and PURβ Bind to a Purine-rich Negative Regulatory Element of the α-Myosin Heavy Chain Gene and Control Transcriptional and Translational Regulation of the Gene Expression

“…TEF-1 and SRF, which also play prominent roles in ␣-MHC gene expression (14,32). Recently, YY1 has been shown to bind to an upstream element in the human ␣-MHC gene promoter where it negatively regulates the gene expression (51). In neurons, YY1 together with PUR␣ controls the cell-specific expression of FE65 gene (24).…”

The Ku Protein Complex Interacts with YY1, Is Up-Regulated in Human Heart Failure, and Represses α Myosin Heavy-Chain Gene Expression

“…Coomassie staining of polyvinylidene difluoride membranes was performed essentially as described elsewhere (38). Following Western blotting experiments, the membrane was stripped of the Abs and stained with Coomassie for 1 h. The membrane was then destained for at least 12 h. The proteins on the membrane were quantified on a LiCor scanner.…”

“…Western blotting assays were performed essentially as described elsewhere (38). Ku Ab was diluted 1:1,000 in 1ϫ phosphate-buffered saline containing 3% bovine serum albumin, 2% normal goat serum, and 0.1% Tween and incubated with the blot for 1 h at room temperature.…”

“…Based on sequence comparison, the human ␣MyHC promoter has putative binding sites for transcription factors that have been shown to be important for the positive regulation of the rat ␣MyHC promoter, e.g., GATA4, NFAT3, TEF, thyroid response, MEF2, and SRF, among others (23). Our laboratory has recently shown that the YY1 transcription factor acts as a repressor of the human ␣MyHC promoter in cardiac cells and that YY1 levels and DNA binding activity are increased in human heart failure (38). This was the first report of a transcriptional repressor of the human ␣MyHC promoter.…”

SMAD-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA4/5/6-dependent chickNkx2.5enhancer

“…6A). YY1 is a ubiquitously expressed, multifunctional transcription factor (Shi et al, 1991), and has been implicated in the positive or negative regulation of cardiac genes, including BNP (Bhalla et al, 2001) and cardiac myofibrillar genes (Chen and Schwartz, 1997;Latinkic et al, 2004;MacLellan et al, 1994;Sucharov et al, 2003). To evaluate if YY1 binds to either of the CCATC repeats, we compared the SR3-binding activities in extracts made from either day 3 chick heart extracts or P19 cells with that of purified YY1.…”