Synergistic activation of cardiac genes by myocardin and Tbx5.

[holt-oram syndrome]

Myocardial differentiation is associated with the activation and expression of an array of cardiac specific genes . However , the transcriptional networks that control cardiac gene expression are not completely understood . Myocardin is a cardiac and smooth muscle -specific expressed transcriptional coactivator of Serum Response Factor (SRF ) and is able to potently activate cardiac and smooth muscle gene expression during development . We hypothesize that myocardin discriminates between cardiac and smooth muscle specific genes by associating with distinct co -factors . Here , we show that myocardin directly interacts with Tbx 5 , a member of the T -box family of transcription factors involved in the Holt-Oram syndrome . Tbx 5 synergizes with myocardin to activate expression of the cardiac specific genes atrial natriuretic factor (ANF ) and alpha myosin heavy chain (α-MHC ), but not that of smooth muscle specific genes SM 22 or smooth muscle myosin heavy chain (SM-MHC ). We found that this synergistic activation of shared target genes is dependent on the binding sites for Tbx 5 , T -box factor -Binding Elements (TBEs ). Myocardin and Tbx 5 physically interact and their interaction domains were mapped to the basic domain and the coil domain of myocardin and Tbx 5 , respectively . Our analysis demonstrates that the Tbx 5 G 8 0 R mutation , which leads to the Holt-Oram syndrome in humans , failed to synergize with myocardin to activate cardiac gene expression . These data uncover a key role for Tbx 5 and myocardin in establishing the transcriptional foundation for cardiac gene activation and suggest that the interaction of myocardin and Tbx 5 maybe involved in cardiac development and diseases .