Reconstruction of regulatory networks through temporal enrichment profiling and its application to H1N1 influenza viral infection.
Reconstruction of regulatory networks through temporal enrichment profiling and its application to H1N1 influenza viral infection.
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DOI：
10.1186/1471-2105-14-s6-s1
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发表时间：
2013
影响因子：
3
通讯作者：
Kleinstein SH
中科院分区：
文献类型：
--
作者：
Zaslavsky E;Nudelman G;Marquez S;Hershberg U;Hartmann BM;Thakar J;Sealfon SC;Kleinstein SH
甲型H1N1流感病毒导致1918年导致全球数百万人死亡的大流行和导致约2万人死亡的2009年大流行。细胞对这种病毒感染的反应包括广泛的基因重新编程，导致对感染控制至关重要的抗病毒状态。识别驱动这些变化的潜在转录网络，以及病毒编码的免疫拮抗剂如何改变这一程序，是系统免疫学中的一个基本挑战。对体外感染季节性H1N1流感A/新喀里多尼亚/20/1999的人类单核细胞来源的树突状细胞(DC)的全基因组基因表达模式进行了测量。为了从机制上解释感染后最初12小时内基因表达变化的时间，我们开发了一种结合全基因组表达动力学和依赖时间的启动子分析的统计严格的浓缩方法。我们的方法，时间依赖的活动链接器(TIDAL)，产生了一个调控网络，将与反应的每个时间阶段相关的转录因子连接成一个连贯的级联。TIDEAD推断了12个转录因子和32个调控连接，这些转录因子和调控连接驱动了对流感的抗病毒反应。为了证明这种方法的普遍性，TIDEAD还被用来生成一个针对麻疹感染的DC反应的网络。TIDAL的软件实现可在http://tsb.mssm.edu/primeportal/?q=tidal_prog.上免费获得我们应用TIDAL来重建单核细胞来源的人类树突状细胞在应对流感和麻疹感染时激活的转录程序。这种以时间为中心的网络重建方法在每个病例中的应用都产生了一个单一的转录级联，除了识别潜在的新的抗病毒因子外，还以高精度和高召回率概括了已知的反应生物学。利用TIDAL重建抗病毒网络的能力使人们能够对抗病毒反应进行对比分析，例如大流行和季节性流感感染之间的差异。
H1N1 influenza viruses were responsible for the 1918 pandemic that caused millions of deaths worldwide and the 2009 pandemic that caused approximately twenty thousand deaths. The cellular response to such virus infections involves extensive genetic reprogramming resulting in an antiviral state that is critical to infection control. Identifying the underlying transcriptional network driving these changes, and how this program is altered by virally-encoded immune antagonists, is a fundamental challenge in systems immunology. Genome-wide gene expression patterns were measured in human monocyte-derived dendritic cells (DCs) infected in vitro with seasonal H1N1 influenza A/New Caledonia/20/1999. To provide a mechanistic explanation for the timing of gene expression changes over the first 12 hours post-infection, we developed a statistically rigorous enrichment approach integrating genome-wide expression kinetics and time-dependent promoter analysis. Our approach, TIme-Dependent Activity Linker (TIDAL), generates a regulatory network that connects transcription factors associated with each temporal phase of the response into a coherent linked cascade. TIDAL infers 12 transcription factors and 32 regulatory connections that drive the antiviral response to influenza. To demonstrate the generality of this approach, TIDAL was also used to generate a network for the DC response to measles infection. The software implementation of TIDAL is freely available at http://tsb.mssm.edu/primeportal/?q=tidal_prog. We apply TIDAL to reconstruct the transcriptional programs activated in monocyte-derived human dendritic cells in response to influenza and measles infections. The application of this time-centric network reconstruction method in each case produces a single transcriptional cascade that recapitulates the known biology of the response with high precision and recall, in addition to identifying potentially novel antiviral factors. The ability to reconstruct antiviral networks with TIDAL enables comparative analysis of antiviral responses, such as the differences between pandemic and seasonal influenza infections.
影响因子：
3
作者：
Nachman I;Regev A
通讯作者：
Regev A