Epstein-Barr Virus Induces Global Changes in Cellular mRNA Isoform Usage That Are Important for the Maintenance of Latency
Epstein-Barr Virus Induces Global Changes in Cellular mRNA Isoform Usage That Are Important for the Maintenance of Latency
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DOI：
10.1128/jvi.02464-13
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发表时间：
2013-11-01
影响因子：
5.4
通讯作者：
Luftig, Micah A.
中科院分区：
文献类型：
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作者：
Homa, Nicholas J.;Salinas, Raul;Luftig, Micah A.
致癌病毒通过宿主转录组的急剧重组来促进细胞增殖。除了调节mRNA丰度，mRNA同工型使用的变化可以对转录组的蛋白质输出产生深远的影响。利用EB病毒（EBV）转化原代B细胞，我们研究了致癌病毒改变其宿主mRNA亚型谱的能力。使用名为SplicerEX的算法和两个互补的Affytron微阵列平台，我们发现了在B细胞转化过程中由EBV调节的433种mRNA亚型变化。这些变化在很大程度上与转化期间观察到的2，163种mRNA丰度变化正交，使得在同种型水平上变化的mRNA中不到三分之一也在总体丰度上变化。虽然我们没有观察到对mRNA同种型变化的机制类别的偏好，但我们检测到相对于未感染的B细胞，EBV转化的细胞中3'非翻译区显著缩短并且盒外显子被排除。mRNA亚型变化的基因本体分析显示核酸结合蛋白显著富集。我们验证了其中几种亚型的变化，并对编码蛋白质XBP1和TCF4的两种mRNA中的变化感兴趣，这两种mRNA都显示出结合并激活主要EBV裂解性反式激活因子BZLF1的启动子。我们的研究表明，EB病毒潜伏感染促进限制BZLF 1激活的XBP1和TCF 4的mRNA亚型的使用。因此，表征EBV感染期间mRNA同工型使用的全局变化确定了维持潜伏感染的新机制。
Oncogenic viruses promote cell proliferation through the dramatic reorganization of host transcriptomes. In addition to regulating mRNA abundance, changes in mRNA isoform usage can have a profound impact on the protein output of the transcriptome. Using Epstein-Barr virus (EBV) transformation of primary B cells, we have studied the ability of an oncogenic virus to alter the mRNA isoform profile of its host. Using the algorithm called SplicerEX with two complementary Affymetrix microarray platforms, we uncovered 433 mRNA isoform changes regulated by EBV during B-cell transformation. These changes were largely orthogonal with the 2,163 mRNA abundance changes observed during transformation, such that less than one-third of mRNAs changing at the level of isoform also changed in overall abundance. While we observed no preference for a mechanistic class of mRNA isoform change, we detected a significant shortening of 3' untranslated regions and exclusion of cassette exons in EBV-transformed cells relative to uninfected B cells. Gene ontology analysis of the mRNA isoform changes revealed significant enrichment in nucleic acid binding proteins. We validated several of these isoform changes and were intrigued by those in two mRNAs encoding the proteins XBP1 and TCF4, which have both been shown to bind and activate the promoter of the major EBV lytic trans-activator BZLF1. Our studies indicate that EBV latent infection promotes the usage of mRNA isoforms of XBP1 and TCF4 that restrict BZLF1 activation. Therefore, characterization of global changes in mRNA isoform usage during EBV infection identifies a new mechanism for the maintenance of latent infection.