Program in Computational Biology and Bioinformatics, Yale University, Bass 426, 266 Whitney Avenue, New Haven, CT 06520, USA.
Sci Signal. 2010 Nov 2;3(146):ra79. doi: 10.1126/scisignal.2001014.
Network connectivity has been related to essentiality: Highly connected proteins (hubs) are more important for cell growth and survival. Although this is intuitively reasonable, another way to assess the role of a regulator is to assign it to a level within a "chain-of-command" hierarchy. Here, we analyzed the effects of network rewiring events on transcriptional regulatory hierarchies in two species. First, we superimposed the phenotypic effects of tampering with specific genes and their regulatory connections directly onto the hierarchies. To study second-order effects, which involved changes in the level of regulators within the hierarchy upon deletions or insertions of other regulators or connections, we reconstructed modified hierarchies. We found that rewiring events that affected upper levels had a more marked effect on cell proliferation rate and survival than did those involving lower levels. Moreover, we showed that the hierarchical level and type of change better reflected the phenotypic effect of rewiring than did the number of changes. We also investigated other features connected to the importance of upper-level regulators: In particular, relative to lower-level regulators, upper-level regulators exhibited a greater range of expression values across species, had fewer functionally redundant copies, and had a shorter half-life. Overall, our analysis shows that broadly constructed hierarchies may better reflect the importance of regulators for cell growth than classifications based on the number of connections (hubbiness).
高度连接的蛋白质（枢纽）对细胞生长和存活更为重要。虽然这是直观合理的，但评估调节剂作用的另一种方法是将其分配到“指挥链”层次结构中的某个级别。在这里，我们分析了两种物种中网络重连事件对转录调控层次结构的影响。首先，我们将干扰特定基因及其调节连接的表型效应直接叠加到层次结构上。为了研究涉及其他调节剂或连接的缺失或插入时层次结构内调节剂水平变化的二阶效应，我们重建了修改后的层次结构。我们发现，影响上层的重连事件对细胞增殖率和存活率的影响比涉及下层的重连事件更为显著。此外，我们表明，与变化数量相比，层次结构级别和变化类型更好地反映了重连的表型效应。我们还研究了与上层调节剂重要性相关的其他特征：特别是与下层调节剂相比，上层调节剂在不同物种中的表达值范围更大，功能冗余拷贝较少，半衰期较短。总的来说，我们的分析表明，与基于连接数量（枢纽性）的分类相比，广泛构建的层次结构可能更好地反映了调节剂对细胞生长的重要性。
