Creemers Esther E, Sutherland Lillian B, McAnally John, Richardson James A, Olson Eric N
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA.
Development. 2006 Nov;133(21):4245-56. doi: 10.1242/dev.02610. Epub 2006 Oct 4.
Myocardin is a transcriptional co-activator of serum response factor (Srf), which is a key regulator of the expression of smooth and cardiac muscle genes. Consistent with its role in regulating cardiovascular development, myocardin is the earliest known marker specific to both the cardiac and smooth muscle lineages during embryogenesis. To understand how the expression of this early transcriptional regulator is initiated and maintained, we scanned 90 kb of genomic DNA encompassing the myocardin gene for cis-regulatory elements capable of directing myocardin transcription in cardiac and smooth muscle lineages in vivo. Here, we describe an enhancer that controls cardiovascular expression of the mouse myocardin gene during mouse embryogenesis and adulthood. Activity of this enhancer in the heart and vascular system requires the combined actions of the Mef2 and Foxo transcription factors. In addition, the Tead transcription factor is required specifically for enhancer activation in neural-crest-derived smooth muscle cells and dorsal aorta. Notably, myocardin also regulates its own enhancer, but in contrast to the majority of myocardin target genes, which are dependent on Srf, myocardin acts through Mef2 to control its enhancer. These findings reveal an Srf-independent mechanism for smooth and cardiac muscle-restricted transcription and provide insight into the regulatory mechanisms responsible for establishing the smooth and cardiac muscle phenotypes during development.
心肌素是血清反应因子（Srf）的转录共激活因子，而血清反应因子是平滑肌和心肌基因表达的关键调节因子。与其在调节心血管发育中的作用一致，心肌素是胚胎发育过程中最早已知的心脏和平滑肌谱系特异性标志物。为了了解这种早期转录调节因子的表达是如何启动和维持的，我们扫描了包含心肌素基因的90 kb基因组DNA，寻找能够在体内心脏和平滑肌谱系中指导心肌素转录的顺式调节元件。在此，我们描述了一种在小鼠胚胎发育和成年期控制小鼠心肌素基因心血管表达的增强子。该增强子在心脏和血管系统中的活性需要Mef2和Foxo转录因子的共同作用。此外，Tead转录因子是神经嵴衍生的平滑肌细胞和背主动脉中增强子激活所特需的。值得注意的是，心肌素也调节其自身的增强子，但与大多数依赖Srf的心肌素靶基因不同，心肌素通过Mef2来控制其增强子。这些发现揭示了一种不依赖Srf的平滑肌和心肌限制性转录机制，并为发育过程中建立平滑肌和心肌表型的调节机制提供了见解。
