Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145, USA.
J Biol Chem. 2010 Jan 8;285(2):1249-58. doi: 10.1074/jbc.M109.046441. Epub 2009 Nov 16.
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.
转录阻遏因子 Hey 家族的成员是碱性螺旋-环-螺旋蛋白，被认为在多种组织中通过 Notch 发挥作用。虽然在成肌细胞中，Notch 的靶标 Hey1 的强制表达足以重现该途径对分化的抑制作用，但 Hey1 如何干扰肌生成转录尚未完全阐明。我们提供了多条证据表明，Hey1 不是针对骨骼肌主调控因子 MyoD 的内在转录活性。相反，我们的结果表明，Hey1 被招募到肌生成蛋白和 Mef2C 的启动子区域，这两个基因的诱导对于肌生成至关重要。Hey1 在 C2C12 成肌细胞中的表达与 MyoD 向这些启动子募集的减少相关，这表明 Hey1 通过与关键的肌生成靶标结合并抑制其表达来抑制肌生成。
