Novel Transcriptional Regulation in Skeletal Muscle Development and Disease

骨骼肌发育和疾病中的新转录调控

• 批准号: nhmrc : 112902
• 负责人: Prof Edna Hardeman
• 金额: $ 22.98万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2000
• 资助国家: 澳大利亚
• 起止时间: 2000-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/novel-transcriptional-regulation-development-disease/81162
• 关键词: Novel; Transcriptional; Regulation; Skeletal; Muscle

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.

人们一直认为，一旦某种特定类型的细胞中的基因被激活，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会出现和消失。与打开并保持打开状态的灯开关相比，至少在肌肉中，基因活动似乎更像是闪烁的灯。如果你拍摄肌肉组织的图像，这只是一个时间快照，那么如果一个基因在观看时暂时“闪烁”，那么它可能不会被激活。这可能发生在所有组织类型中，但在肌肉中更容易检测到，因为肌肉细胞大而多核，而不是小而单核。这种现象在肌肉细胞中更容易被发现的另一个原因是，肌肉细胞是非常动态的细胞，可以经历相当彻底的形状变化。一个活跃生长或肥大的肌肉细胞可能所有的基因都处于高水平的转录活动，以支持快速生长。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)这可能是几乎所有细胞类型中发生的基因调控的基本机制。因此，我们的发现将为研究这种新机制所涉及的分子类型开辟一个领域。(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，以及神经损伤或遗传性肌肉疾病引起的肌肉萎缩的机制。(3)这一机制可以解释外源DNA通过基因治疗途径在肌肉细胞中的表达。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，使其相信自己处于永久生长模式。