Rewiring of Transcriptional Regulatory Networks: Hierarchy, Rather than Connectivity, Better Reflects the Importance of Regulators
Rewiring of Transcriptional Regulatory Networks: Hierarchy, Rather than Connectivity, Better Reflects the Importance of Regulators
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DOI：
10.1126/scisignal.2001014
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发表时间：
2010-11-02
影响因子：
7.3
通讯作者：
Gerstein, Mark B.
中科院分区：
文献类型：
--
作者：
Bhardwaj, Nitin;Kim, Philip M.;Gerstein, Mark B.
网络连接与重要性有关：高度连接的蛋白质（枢纽）对细胞生长和存活更重要。虽然这在直觉上是合理的，但评估监管机构作用的另一种方法是将其分配到“指挥链”等级制度中的一个级别。在这里，我们分析了网络重布线事件对两个物种的转录调控层次的影响。首先，我们将篡改特定基因及其调控连接的表型效应直接叠加到层次结构上。为了研究二阶效应，其中涉及的层次结构内的监管机构的水平的变化后，删除或插入其他监管机构或连接，我们重建修改后的层次结构。我们发现，影响较高水平的重新布线事件对细胞增殖率和存活率的影响比涉及较低水平的更明显。此外，我们发现，层次和类型的变化更好地反映了重布线的表型效应比变化的数量。我们还研究了与上层调节剂的重要性相关的其他特征：特别是，相对于较低水平的调节剂，上层调节剂在不同物种中表现出更大的表达值范围，具有更少的功能冗余拷贝，并且具有更短的半衰期。总的来说，我们的分析表明，广泛构建的层次结构可能更好地反映了调控细胞生长的重要性，而不是基于连接数量（hubbiness）的分类。
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).