Computational Identification of Kinases That Control Axon Growth in Mouse.
Computational Identification of Kinases That Control Axon Growth in Mouse.
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DOI：
10.1177/2472555220930697
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发表时间：
2020-08
期刊：
影响因子：
--
通讯作者：
Wuchty S
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文献类型：
--
作者：
Devkota P;Danzi MC;Lemmon VP;Bixby JL;Wuchty S
从基础科学和转化医学的角度来看，确定控制各种生物过程的信号通路和转录网络是一个重大挑战。由于这种分析可以指向关键的疾病驱动节点，以达到治疗目的，我们结合了表型筛选实验和小鼠神经元基因表达研究的数据，以确定通过分子相互作用网络使用网络传播方法的信息流。我们假设，控制和受伤的条件之间的信息流的差异优先相关的驱动程序节点，导致这种状态的变化。识别可能从潜在源节点到一组转录因子（TF）（称为汇）的路径，我们发现在轴突损伤模型中，激酶在向TF发送显著不同数量的信息的源基因中富集。此外，发现在轴突生长过程中具有差异活性的TF在接收来自源基因的显著改变的信息量的汇基因组中富集。值得注意的是，即使将源基因的集合限制为仅观察到支持或阻碍神经突生长的那些激酶，这样的富集水平也保持不变。通过这种方式，我们发现了一组71个源基因，它们向轴突生长相关的TF发送了显著不同水平的信息。我们分析了轴突损伤时它们的信息流变化及其对预测促进或拮抗轴突生长的TF的影响。最后，我们绘制了这些源基因和它们的轴突生长相关的汇转录因子之间的相互作用和信息流变化的网络图。
The determination of signaling pathways and transcriptional networks that control various biological processes is a major challenge from both basic science and translational medicine perspectives. As such analysis can point to critical disease driver nodes to target for therapeutic purposes, we combined data from phenotypic screening experiments and gene expression studies of mouse neurons to determine information flow through a molecular interaction network using a network propagation approach. We hypothesized that differences in information flow between control and injured conditions prioritize relevant driver nodes that cause this state change. Identifying paths likely taken from potential source nodes to a set of transcription factors (TFs), called sinks, we found that kinases are enriched among source genes sending significantly different amounts of information to TFs in an axonal injury model. Additionally, TFs found to be differentially active during axon growth were enriched in the set of sink genes that received significantly altered amounts of information from source genes. Notably, such enrichment levels hold even when restricting the set of source genes to only those kinases observed to support or hamper neurite growth. That way, we found a set of 71 source genes that send significantly different levels of information to axon growth-relevant TFs. We analyzed their information flow changes in response to axonal injury and their influences on TFs predicted to facilitate or antagonize axon growth. Finally, we drew a network diagram of the interactions and changes in information flow between these source genes and their axon growth-relevant sink TFs.
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