Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
PLoS Comput Biol. 2012;8(7):e1002603. doi: 10.1371/journal.pcbi.1002603. Epub 2012 Jul 26.
Traditionally the gene expression pathway has been regarded as being comprised of independent steps, from RNA transcription to protein translation. To date there is increasing evidence of coupling between the different processes of the pathway, specifically between transcription and splicing. To study the interplay between these processes we derived a transcription-splicing integrated network. The nodes of the network included experimentally verified human proteins belonging to three groups of regulators: transcription factors, splicing factors and kinases. The nodes were wired by instances of predicted transcriptional and alternative splicing regulation. Analysis of the network indicated a pervasive cross-regulation among the nodes; specifically, splicing factors are significantly more connected by alternative splicing regulatory edges relative to the two other subgroups, while transcription factors are more extensively controlled by transcriptional regulation. Furthermore, we found that splicing factors are the most regulated of the three regulatory groups and are subject to extensive combinatorial control by alternative splicing and transcriptional regulation. Consistent with the network results, our bioinformatics analyses showed that the subgroup of kinases have the highest density of predicted phosphorylation sites. Overall, our systematic study reveals that an organizing principle in the logic of integrated networks favor the regulation of regulatory proteins by the specific regulation they conduct. Based on these results, we propose a new regulatory paradigm postulating that gene expression regulation of the master regulators in the cell is predominantly achieved by cross-regulation.
传统上，基因表达途径被认为是由独立的步骤组成的，从 RNA 转录到蛋白质翻译。迄今为止，越来越多的证据表明该途径的不同过程之间存在耦合，特别是转录和剪接之间。为了研究这些过程之间的相互作用，我们推导出了一个转录-剪接综合网络。该网络的节点包括属于三个调节因子组的经实验验证的人类蛋白质：转录因子、剪接因子和激酶。节点通过预测的转录和可变剪接调节实例连接。网络分析表明节点之间存在普遍的交叉调节；具体来说，与其他两个亚组相比，剪接因子通过可变剪接调节边缘的连接更为显著，而转录因子受到转录调节的控制更为广泛。此外，我们发现剪接因子是三个调节组中受调节最多的因子，并且受到可变剪接和转录调节的广泛组合控制。与网络结果一致，我们的生物信息学分析表明，激酶亚组具有预测磷酸化位点的最高密度。总体而言，我们的系统研究表明，综合网络逻辑中的一个组织原则有利于通过它们进行的特定调节来调节调节蛋白。基于这些结果，我们提出了一个新的调节范例，即细胞中主调控因子的基因表达调节主要通过交叉调节来实现。
