Novel Transcriptional Regulation in Skeletal Muscle Development and Disease

人们一直认为，一旦基因在特定类型的细胞中被激活，它们就会保持开启状态。从这个实验室描述的工作中，我们现在知道基因活动可能来来去去。看起来，至少在肌肉中，基因活动更像是闪烁的灯，而不是已经打开并保持打开的灯开关的类比。如果你拍摄一张肌肉组织的图像，这只是一张时间的快照，如果一个基因在观看时暂时闪现，它可能看起来不会被激活。这可能发生在所有类型的组织中，但在肌肉中更容易检测到，因为细胞大，有多个核，而不是小的，只有一个核。在肌肉细胞中更容易检测到这种现象的另一个原因是，它们是非常有活力的细胞，可以经历相当剧烈的形状变化。活跃生长或肥大的肌肉细胞可能有其所有的基因处于高度转录活性，以支持快速生长。然而，一旦肌肉细胞达到合适的大小，肌肉基因就会切换到闪烁的转录模式，以维持而不是构建结构。意义：(1)这可能是基因调控的基本机制，几乎在所有类型的细胞中都会发生。因此，我们的发现将为这一新机制中涉及的分子类型开辟一个研究领域。(2)我们的研究将有助于更好地理解运动和药物引起的肌肉细胞肥大的机制，以及由于神经损伤或遗传性肌肉疾病而导致的萎缩。(3)这一机制可能解释了通过基因治疗途径在肌肉细胞中表达外源DNA的原因。我们的发现可能会导致一种更有效的方式来表达引入的基因，这可能需要欺骗肌肉纤维，使其相信它处于永久生长模式。

It has been assumed that once genes are activated in a particular type of cell, they remain 'on'. From work described in this laboratory, we now know that gene activity may come and go. Instead of the analogy of a light switch that has been turned on and stays on, it appears that at least in muscle, gene activity is more like blinking lights. If you take an image of muscle tissue, which is just a snapshot in time, a gene may not appear to be activated if it was temporarily 'flashing off' at the time of viewing. This may occur in all tissue types, but it is more easily detected in muscle because the cell is large with many nuclei, rather than small with a single nucleus. Another reason why this phenomenon is more readily detectable in muscle cells is that they are very dynamic cells that can undergo fairly radical changes in shape. An actively growing or hypertrophying muscle cell may have all of its genes at a high pitch of transcriptional activity to support rapid growth. However, once a muscle cell has reached its appropriate size, then muscle genes switch to a flashing mode of transcription to maintain rather than build structures. SIGNIFICANCE: (1) This may be a fundamental mechanism of gene regulation that occurs in virtually all cell types. As such, our finding will open an area of research into the types of molecules involved in this novel mechanism. (2) Our studies will result in a better understanding of the mechanisms of muscle cell hypertrophy in response to excercise and drugs, as well as atrophy due to nerve damage or inherited muscle disease. (3) This mechanism may explain the expression of foreign DNA in muscle cells delivered via gene therapy approaches. Our findings could result in a more efficacious means of expressing the introduced gene that might require tricking the muscle fibre into believing that it is in a perpetual growth mode.