Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines
Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines
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DOI：
10.3390/ijms20051182
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发表时间：
2019-03-01
影响因子：
5.6
通讯作者：
Relogio, Angela
中科院分区：
文献类型：
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作者：
Genov, Nikolai;Basti, Alireza;Relogio, Angela
选择性剪接在许多细胞过程中起重要作用，并且异常剪接决定与癌症相关。虽然一些研究指出，可变剪接及其效应机制的调节在一个时间依赖性的方式，这种调节的程度和后果仍然知之甚少。在目前的工作中，我们研究了时间依赖性生产的异构体在两个霍奇金淋巴瘤细胞系的不同进展阶段（HD-MY-Z，第IIIb期和L-1236，第IV期）相比，B淋巴母细胞样细胞系（LCL-HO），重点是肿瘤坏死因子（TNF）通路相关的元素。为此，我们使用了来自上述细胞系的新生成的时程RNA测序数据，并应用计算管道来及时识别具有亚型转换行为的基因。我们分析了所确定的事件的时间分布，并详细评估了所选顶部开关基因的亚型表达改变的潜在功能影响。我们的数据表明，TNF途径内的元素经历了一个时间依赖性的变化，异构体的生产与细胞迁移，增殖和凋亡的推定影响。这些基因包括TRAF 1、TNFRSF 12 A和NFKB 2。我们的研究结果表明，时间选择性剪接在异构体产生中的作用，这可能会改变TNF途径的结果并影响肿瘤发生。
Alternative splicing plays an important role in numerous cellular processes and aberrant splice decisions are associated with cancer. Although some studies point to a regulation of alternative splicing and its effector mechanisms in a time-dependent manner, the extent and consequences of such a regulation remains poorly understood. In the present work, we investigated the time-dependent production of isoforms in two Hodgkin lymphoma cell lines of different progression stages (HD-MY-Z, stage IIIb and L-1236, stage IV) compared to a B lymphoblastoid cell line (LCL-HO) with a focus on tumour necrosis factor (TNF) pathway-related elements. For this, we used newly generated time-course RNA-sequencing data from the mentioned cell lines and applied a computational pipeline to identify genes with isoform-switching behaviour in time. We analysed the temporal profiles of the identified events and evaluated in detail the potential functional implications of alterations in isoform expression for the selected top-switching genes. Our data indicate that elements within the TNF pathway undergo a time-dependent variation in isoform production with a putative impact on cell migration, proliferation and apoptosis. These include the genes TRAF1, TNFRSF12A and NFKB2. Our results point to a role of temporal alternative splicing in isoform production, which may alter the outcome of the TNF pathway and impact on tumorigenesis.