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。从这个实验室的工作中，我们现在知道基因的活动可能会来来去去。与其说是一个灯开关被打开并保持打开状态，不如说至少在肌肉中，基因活动更像是闪烁的灯光。如果你拍摄肌肉组织的图像，这只是一个时间快照，如果一个基因在观看时暂时“闪烁”，它可能看起来没有被激活。这可能发生在所有组织类型中，但它更容易在肌肉中检测到，因为细胞大，有许多核，而不是小，只有一个核。这种现象在肌肉细胞中更容易检测到的另一个原因是，它们是非常动态的细胞，可以经历相当彻底的形状变化。一个活跃的生长或肥大的肌肉细胞可能有它的所有基因在一个高音调的转录活性，以支持快速增长。然而，一旦肌肉细胞达到适当的大小，肌肉基因就会切换到一种闪烁的转录模式，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，几乎发生在所有细胞类型中。因此，我们的发现将开辟一个研究领域，研究参与这种新机制的分子类型。(2)我们的研究将导致更好地了解肌肉细胞肥大的机制，以应对运动和药物，以及萎缩由于神经损伤或遗传性肌肉疾病。(3)这种机制可以解释通过基因治疗方法递送的外源DNA在肌细胞中的表达。我们的发现可能会导致一种更有效的表达引入基因的方法，这种方法可能需要欺骗肌肉纤维，使其相信它处于永久的生长模式。

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.