Transcriptional analysis of the titin cap gene.
Transcriptional analysis of the titin cap gene.
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DOI：
10.1007/s00438-011-0603-6
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发表时间：
2011-03
期刊：
影响因子：
--
通讯作者：
Davie JK
中科院分区：
文献类型：
--
作者：
Zhang S;Londhe P;Zhang M;Davie JK
titin cap（Tcap）（也称为telethonin）的突变会导致2G型肢带肌营养不良症（LGMD 2G）。Tcap是肌联蛋白相互作用的Z盘蛋白之一，参与正常肌节结构的调节和发育。鉴于Tcap在建立和维持正常骨骼肌结构中的重要作用，我们有兴趣确定该基因在成肌细胞中表达所需的调控元件。我们已经定义了一个高度保守的421 bp的启动子近端启动子片段，包含两个E盒和多个推定的Mef2结合序列。该启动子在NIH3T3成纤维细胞中可被MyoD和myogenin激活，并在C2C12细胞中维持内源性Tcap的分化细胞特异性表达模式。我们发现，虽然两个E盒所需的MyoD或肌细胞生成素在NIH3T3细胞中的完全激活，启动子近端E盒有一个更大的贡献，激活该启动子在C2C12细胞和激活MyoD在NIH3T3细胞。总之，这些数据表明MyoD在通过启动子近端E盒激活Tcap表达中的重要作用。我们还表明，肌细胞生成素是所需的正常表达在体内和物理结合的Tcap启动子在胚胎发生。
Mutations in titin cap (Tcap), also known as telethonin, cause limb-girdle muscular dystrophy type 2G (LGMD2G). Tcap is one of the titin interacting Z-disc proteins involved in the regulation and development of normal sarcomeric structure. Given the essential role of Tcap in establishing and maintaining normal skeletal muscle architecture, we were interested in determining the regulatory elements required for expression of this gene in myoblasts. We have defined a highly conserved 421 bp promoter proximal promoter fragment that contains two E boxes and multiple putative Mef2 binding sequences. This promoter can be activated by MyoD and myogenin in NIH3T3 fibroblast cells, and maintains the differentiated cell-specific expression pattern of the endogenous Tcap in C2C12 cells. We find that while both E boxes are required for full activation by MyoD or myogenin in NIH3T3 cells, the promoter proximal E box has a greater contribution to activation of this promoter in C2C12 cells and to activation by MyoD in NIH3T3 cells. Together, the data suggest an important role for MyoD in activating Tcap expression through the promoter proximal E box. We also show that myogenin is required for normal expression in vivo and physically binds to the Tcap promoter during embryogenesis.
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