The Notch Effector Hey1 Associates with Myogenic Target Genes to Repress Myogenesis
The Notch Effector Hey1 Associates with Myogenic Target Genes to Repress Myogenesis
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DOI：
10.1074/jbc.m109.046441
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发表时间：
2010-01-08
影响因子：
4.8
通讯作者：
Kadesch, Tom
中科院分区：
文献类型：
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作者：
Buas, Matthew F.;Kabak, Shara;Kadesch, Tom
Hey家族转录抑制因子的成员是碱性螺旋-环-螺旋蛋白，被认为在不同组织中作用于Notch下游。虽然强迫表达Hey1（Notch在成肌细胞中的靶点）足以概括该途径对分化的抑制作用，但Hey1如何干扰肌原性转录尚未完全阐明。我们提供了多条证据表明Hey1不靶向骨骼肌主调节因子MyoD的内在转录活性。相反，我们的研究结果表明，Hey1被招募到肌细胞生成素和Mef2C的启动子区域，这两个基因的诱导对肌细胞生成至关重要。Hey1在C2C12成肌细胞中的表达与MyoD向这些启动子的募集减少相关，认为Hey1通过与关键肌源性靶点相关并抑制其表达来抑制肌源性。
Members of the Hey family of transcriptional repressors are basic helix-loop-helix proteins that are thought to act downstream of Notch in diverse tissues. Although forced expression of Hey1, a target of Notch in myoblasts, is sufficient to recapitulate inhibitory effects of the pathway on differentiation, how Hey1 interferes with myogenic transcription has not been fully elucidated. We provide multiple lines of evidence that Hey1 does not target the intrinsic transcriptional activity of the skeletal muscle master regulator MyoD. Our results indicate instead that Hey1 is recruited to the promoter regions of myogenin and Mef2C, two genes whose induction is critical for myogenesis. Expression of Hey1 in C2C12 myoblasts correlates with reduced recruitment of MyoD to these promoters, arguing that Hey1 inhibits myogenesis by associating with and repressing expression of key myogenic targets.