Waardenberg Ashley J, Reverter Antonio, Wells Christine A, Dalrymple Brian P
CSIRO, Food Futures Flagship, Queensland Bioscience Precinct, 306 Carmody Road, St, Lucia, QLD 4067, Australia.
BMC Syst Biol. 2008 Oct 22;2:88. doi: 10.1186/1752-0509-2-88.
Myogenesis is an ordered process whereby mononucleated muscle precursor cells (myoblasts) fuse into multinucleated myotubes that eventually differentiate into myofibres, involving substantial changes in gene expression and the organisation of structural components of the cells. To gain further insight into the orchestration of these structural changes we have overlaid the spatial organisation of the protein components of a muscle cell with their gene expression changes during differentiation using a new 3D visualisation tool: the Virtual Muscle 3D (VMus3D).
Sets of generic striated muscle costamere, Z-disk and filament proteins were constructed from the literature and protein-interaction databases. Expression profiles of the genes encoding these proteins were obtained from mouse C2C12 cells undergoing myogenesis in vitro, as well as a mouse tissue survey dataset. Visualisation of the expression data in VMus3D yielded novel observations with significant relationships between the spatial location and the temporal expression profiles of the structural protein products of these genes. A muscle specificity index was calculated based on muscle expression relative to the median expression in all tissues and, as expected, genes with the highest muscle specificity were also expressed most dynamically during differentiation. Interestingly, most genes encoding costamere as well as some Z-disk proteins appeared to be broadly expressed across most tissues and showed little change in expression during muscle differentiation, in line with the broader cellular role described for some of these proteins.
By studying gene expression patterns from a structural perspective we have demonstrated that not all genes encoding proteins that are part of muscle specific structures are simply up-regulated during muscle cell differentiation. Indeed, a group of genes whose expression program appears to be minimally affected by the differentiation process, code for proteins participating in vital skeletal muscle structures. Expression alone is a poor metric of gene behaviour. Instead, the "connectivity model of muscle development" is proposed as a mechanism for muscle development: whereby the closer to the myofibril core of muscle cells, the greater the gene expression changes during muscle differentiation and the greater the muscle specificity.
肌生成是一个有序的过程，在此过程中，单核肌肉前体细胞（成肌细胞）融合形成多核肌管，最终分化为肌纤维，这涉及基因表达以及细胞结构成分组织的重大变化。为了进一步深入了解这些结构变化的调控机制，我们使用一种新的3D可视化工具：虚拟肌肉3D（VMus3D），将肌肉细胞蛋白质成分的空间组织与其在分化过程中的基因表达变化进行了叠加。
从文献和蛋白质相互作用数据库中构建了一组通用的横纹肌肌膜、Z盘和细丝蛋白。编码这些蛋白质的基因的表达谱来自体外进行肌生成的小鼠C2C12细胞，以及一个小鼠组织调查数据集。在VMus3D中对表达数据进行可视化分析，得出了新的观察结果，这些基因的结构蛋白产物的空间位置与时间表达谱之间存在显著关系。基于相对于所有组织中值表达的肌肉表达计算了肌肉特异性指数，正如预期的那样，具有最高肌肉特异性的基因在分化过程中表达也最活跃。有趣的是，大多数编码肌膜以及一些Z盘蛋白的基因似乎在大多数组织中广泛表达，并且在肌肉分化过程中表达变化很小，这与其中一些蛋白质所描述的更广泛的细胞作用一致。
通过从结构角度研究基因表达模式，我们证明并非所有编码肌肉特异性结构组成部分蛋白质的基因在肌肉细胞分化过程中都会简单地上调。实际上，一组其表达程序似乎受分化过程影响最小的基因，编码参与重要骨骼肌结构的蛋白质。仅表达是衡量基因行为的一个不佳指标。相反，提出了“肌肉发育的连接模型”作为肌肉发育的一种机制：即离肌肉细胞肌原纤维核心越近，在肌肉分化过程中基因表达变化越大，肌肉特异性也越高。
