Modulation of Gene Expression Regulated by the Transcription Factor NF-κB/RelA
Modulation of Gene Expression Regulated by the Transcription Factor NF-κB/RelA
复制标题
NFkB/RelA 调节基因表达
DOI：
10.1074/jbc.m113.539965
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发表时间：
2014-04-25
影响因子：
4.8
通讯作者：
Kudlicki, Andrzej
中科院分区：
文献类型：
--
作者：
Li, Xueling;Zhao, Yingxin;Kudlicki, Andrzej
背景：相互作用的蛋白调节NF-B/RelA转录因子的活性及其靶标的表达。结果：通过分析基因表达、蛋白结合和DNA结合，我们推断并鉴定了8349种这样的调控。结论：不同的调节剂组影响不同的通路。意义：对NF-B/RelA的活性有了新的认识。我们的推理模型可以应用于其他过程和途径。调节因子（Ms）是调节转录因子（TFs）活性并影响其靶基因（TGs）表达的蛋白质。为了发现NF-B/RelA的调节因子，我们首先使用液相色谱-串联质谱（LC-MS/MS）鉴定了365个NF-B/RelA结合蛋白。我们使用概率模型从LC-MS/MS和ChIP- seq （ChIP随后进行下一代测序）数据、已发表的RelA调节剂和TG以及基因表达谱摘要中推断出8349个（M, NF-B/RelA， TG）三联体及其调节作用模式。衍生的调节网络的分层聚类揭示了功能子网络，并提出了调节RelA转录活性的新途径。TGs数量最多和作用模式非随机分布最多的调制器（由香农熵测量）与已发表的报告一致。我们的结果为实验验证提供了一系列可检验的假设。我们确定的NF-B/RelA调制器之一是STAT1。通过lc选择反应监测-质谱和人纤维肉瘤细胞中STAT1缺失的结果验证了推断的（STAT1, NF-B/RelA， TG）三联体。总的来说，我们已经鉴定出562种NF-B/RelA调节剂，这些调节剂是潜在的药物靶点，并阐明了通过调节剂实现NF-B/RelA多种功能的机制。我们的方法可以很容易地应用于其他tf。
Background: Interacting proteins modulate the activity of NF-B/RelA transcription factor and expression of its targets. Results: By analyzing gene expression, protein binding, and DNA binding, we inferred and characterized 8349 such modulations. Conclusion: Different modulator groups affect separate pathways. Significance: We provide new insight into the activity of NF-B/RelA. Our inference model can be applied to other processes and pathways.Modulators (Ms) are proteins that modify the activity of transcription factors (TFs) and influence expression of their target genes (TGs). To discover modulators of NF-B/RelA, we first identified 365 NF-B/RelA-binding proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used a probabilistic model to infer 8349 (M, NF-B/RelA, TG) triplets and their modes of modulatory action from our combined LC-MS/MS and ChIP-Seq (ChIP followed by next generation sequencing) data, published RelA modulators and TGs, and a compendium of gene expression profiles. Hierarchical clustering of the derived modulatory network revealed functional subnetworks and suggested new pathways modulating RelA transcriptional activity. The modulators with the highest number of TGs and most non-random distribution of action modes (measured by Shannon entropy) are consistent with published reports. Our results provide a repertoire of testable hypotheses for experimental validation. One of the NF-B/RelA modulators we identified is STAT1. The inferred (STAT1, NF-B/RelA, TG) triplets were validated by LC-selected reaction monitoring-MS and the results of STAT1 deletion in human fibrosarcoma cells. Overall, we have identified 562 NF-B/RelA modulators, which are potential drug targets, and clarified mechanisms of achieving NF-B/RelA multiple functions through modulators. Our approach can be readily applied to other TFs.