The Transcription Factor TEAD1 Represses Smooth Muscle-specific Gene Expression by Abolishing Myocardin Function

Background: The function of TEAD1 in the expression of smooth muscle-specific genes is unknown. Results: TEAD1 is induced after arterial injury and suppresses the expression of smooth muscle-specific genes by abolishing myocardin function. Conclusion: TEAD1 is a novel repressor for smooth muscle contractile gene expression. Significance: This study provides novel evidence that TEAD1 is critical for promoting phenotypic switching in smooth muscle cells. The TEAD (transcriptional enhancer activator domain) proteins share an evolutionarily conserved DNA-binding TEA domain, which binds to the MCAT cis-acting regulatory element. Previous studies have shown that TEAD proteins are involved in regulating the expression of smooth muscle -actin. However, it remains undetermined whether TEAD proteins play a broader role in regulating expression of other genes in vascular smooth muscle cells. In this study, we show that the expression of TEAD1 is significantly induced during smooth muscle cell phenotypic modulation and negatively correlates with smooth muscle-specific gene expression. We further demonstrate that TEAD1 plays a novel role in suppressing expression of smooth muscle-specific genes, including smooth muscle -actin, by abolishing the promyogenic function of myocardin, a key mediator of smooth muscle differentiation. Mechanistically, we found that TEAD1 competes with myocardin for binding to serum response factor (SRF), resulting in disruption of myocardin and SRF interactions and thereby attenuating expression of smooth muscle-specific genes. This study provides the first evidence demonstrating that TEAD1 is a novel general repressor of smooth muscle-specific gene expression through interfering with myocardin binding to SRF.