Alternative splicing networks regulated by signaling in human T cells
Alternative splicing networks regulated by signaling in human T cells
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DOI：
10.1261/rna.032243.112
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发表时间：
2012-05-01
期刊：
影响因子：
4.5
通讯作者：
Lynch, Kristen W.
中科院分区：
文献类型：
--
作者：
Martinez, Nicole M.;Pan, Qun;Lynch, Kristen W.
有效免疫反应的形成和执行需要有能力的 T 细胞的成熟以及抗原攻击后细胞活性的剧烈变化。细胞功能的这种变化取决于蛋白质表达的调节改变。先前的研究重点是定义 T 细胞成熟和抗原刺激过程中调节蛋白质表达的转录变化。在这里，我们全面分析了 T 细胞刺激过程中基因调控的另一个关键过程，即选择性剪接。具体来说，我们使用 RNA-seq 分析来识别 168 个基因中的 178 个外显子，这些外显子在响应人类 T 细胞系的刺激时表现出强烈的包含变化。这些信号响应外显子在具有与免疫反应特别相关的功能注释的基因中显着富集，支持T细胞刺激后选择性剪接的全局协调的重要作用。这些基因中的绝大多数还表现出初始 T 细胞和活化原代 T 细胞之间的差异选择性剪接。培养T细胞和原代T细胞中剪接对各种刺激的反应性的比较进一步揭示了信号诱导的选择性剪接事件的至少三个不同网络。重要的是，我们发现每个调控网络都与不同的序列特征具体相关，这表明它们由独立的调控机制控制。因此，这些结果为阐明 T 细胞刺激期间选择性剪接的信号通路特异性调节机制提供了基础。
The formation and execution of a productive immune response requires the maturation of competent T cells and a robust change in cellular activity upon antigen challenge. Such changes in cellular function depend on regulated alterations to protein expression. Previous research has focused on defining transcriptional changes that regulate protein expression during T-cell maturation and antigen stimulation. Here, we globally analyze another critical process in gene regulation during T-cell stimulation, alternative splicing. Specifically, we use RNA-seq profiling to identify 178 exons in 168 genes that exhibit robust changes in inclusion in response to stimulation of a human T-cell line. Supporting an important role for the global coordination of alternative splicing following T-cell stimulation, these signal-responsive exons are significantly enriched in genes with functional annotations specifically related to immune response. The vast majority of these genes also exhibit differential alternative splicing between naive and activated primary T cells. Comparison of the responsiveness of splicing to various stimuli in the cultured and primary T cells further reveals at least three distinct networks of signal-induced alternative splicing events. Importantly, we find that each regulatory network is specifically associated with distinct sequence features, suggesting that they are controlled by independent regulatory mechanisms. These results thus provide a basis for elucidating mechanisms of signal pathway-specific regulation of alternative splicing during T-cell stimulation.