Integrative gene network analysis identifies key signatures, intrinsic networks and host factors for influenza virus A infections.
Integrative gene network analysis identifies key signatures, intrinsic networks and host factors for influenza virus A infections.
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DOI：
10.1038/s41540-017-0036-x
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发表时间：
2017
影响因子：
4
通讯作者：
Zhang B
中科院分区：
文献类型：
--
作者：
Forst CV;Zhou B;Wang M;Chou TW;Mason G;Song WM;Schadt E;Ghedin E;Zhang B
甲型流感病毒具有10-14种蛋白质的有限编码能力，其生命周期的许多方面都需要宿主细胞机制。对这些宿主细胞需求的了解不仅揭示了病毒利用或免疫系统触发的分子途径，而且还为抗病毒药物开发提供了进一步的靶点。为了揭示流感感染的新途径和关键靶点，我们从12个基于细胞的流感感染基因表达研究中收集了大量数据，用于综合网络分析。我们系统地鉴定了流感感染诱导的差异表达基因和基因共表达网络。我们发现胞质分裂贡献因子5（DOCK 5）在流感病毒复制中可能起重要作用。CRISPR/Cas9敲除DOCK 5减少了流感病毒的复制，表明DOCK 5是病毒生命周期的关键调节因子。通过DOCK 5敲除实验确定的DOCK 5靶点有力地验证了预测的基因特征和网络。本研究系统地揭示和验证了流感病毒感染中分子反应的基本模式、基因共调节的内在结构和新的关键靶点。流感感染的分子应答涉及大量以复杂分子网络形式存在的相互作用途径。大多数关于流感感染的研究主要集中在测试特定的分子和假设，数据有限。因此，缺乏流感感染中分子相互作用的全局图。在这项研究中，我们对来自12项基于细胞的流感感染基因表达研究的大量数据进行了综合网络分析。通过结合差异表达、共表达网络和基因敲除实验，我们发现并验证了流感感染中分子反应的基本模式、基因共调控的内在结构和新的关键靶点。我们的研究结果为其他功能研究铺平了道路，以确定针对流感感染的新治疗靶点。
Influenza A virus, with the limited coding capacity of 10–14 proteins, requires the host cellular machinery for many aspects of its life cycle. Knowledge of these host cell requirements not only reveals molecular pathways exploited by the virus or triggered by the immune system, but also provides further targets for antiviral drug development. To uncover novel pathways and key targets of influenza infection, we assembled a large amount of data from 12 cell-based gene-expression studies of influenza infection for an integrative network analysis. We systematically identified differentially expressed genes and gene co-expression networks induced by influenza infection. We revealed the dedicator of cytokinesis 5 (DOCK5) played potentially an important role for influenza virus replication. CRISPR/Cas9 knockout of DOCK5 reduced influenza virus replication, indicating that DOCK5 is a key regulator for the viral life cycle. DOCK5’s targets determined by the DOCK5 knockout experiments strongly validated the predicted gene signatures and networks. This study systematically uncovered and validated fundamental patterns of molecular responses, intrinsic structures of gene co-regulation, and novel key targets in influenza virus infection. Molecular response to influenza infection involves a large number of interacting pathways in the form of complex molecular networks. Most studies on influenza infection have largely focused on testing specific molecules and hypotheses with limited data. Therefore, a global picture of molecular interactions in influenza infection is missing. In this study, we performed an integrative network analysis on a large amount of data from 12 cell-based gene expression studies of influenza infections. By combining differential expression, co-expression networks, and gene knockout experiments, we uncovered and validated fundamental patterns of molecular responses, intrinsic structures of gene co-regulation, and novel key targets in influenza infection. Our findings pave the way for other functional investigations into identifying novel therapeutic targets against influenza infection.
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DOI：
10.1038/nri3665
发表时间：
2014-05
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
Hasan N;Corbin D;Hu C
通讯作者：
Hu C
影响因子：
4.4
作者：
Kroeker AL;Ezzati P;Halayko AJ;Coombs KM
通讯作者：
Coombs KM
影响因子：
5.4
作者：
Forte, Eleonora;Luftig, Micah A.
通讯作者：
Luftig, Micah A.
影响因子：
--
作者：
Ding, Xiaoran;Yang, Jing;Wang, Shengqi
通讯作者：
Wang, Shengqi