An atlas of transposable element-derived alternative splicing in cancer
An atlas of transposable element-derived alternative splicing in cancer
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DOI：
10.1098/rstb.2019.0342
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发表时间：
2020-03-30
影响因子：
6.3
通讯作者：
Jordan, I. King
中科院分区：
文献类型：
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作者：
Clayton, Evan A.;Rishishwar, Lavanya;Jordan, I. King
转座元件 (TE) 衍生的序列占人类基因组的一半以上，它们的存在已被证明可以通过多种不同的方式改变基因表达，包括生成选择性剪接的转录亚型。选择性剪接与许多不同癌症的肿瘤发生有关。本研究的目的是广泛描述人类 TE 在癌症中生成选择性剪接转录亚型的作用。为此，我们筛选了与正常组织和癌症组织中不同使用的选择性剪接位点共定位的 TE 衍生序列的存在。我们分析了一组全面的选择性剪接变体，其特征在于 13 种癌症类型的 614 个匹配的正常肿瘤组织对，结果发现了分布在 723 个癌症相关基因中的 4820 个 TE 生成的选择性剪接事件。研究发现，短散布核元件 (Alu) 和长散布核元件 (L1) 贡献了癌症基因中 TE 生成的大部分选择性剪接位点。许多癌症相关基因，包括 MYH11、WHSC1 和 CANT1，已被证明在多种癌症类型中过度表达 TE 衍生的亚型。 TE 衍生的亚型也与癌症特异性融合转录本相关，这表明通过分散的 TE 重复介导的反式剪接产生转录组多样性的新机制。本文是讨论会议问题“转座子与基因调控之间的十字路口”的一部分。
Transposable element (TE)-derived sequences comprise more than half of the human genome, and their presence has been documented to alter gene expression in a number of different ways, including the generation of alternatively spliced transcript isoforms. Alternative splicing has been associated with tumorigenesis for a number of different cancers. The objective of this study was to broadly characterize the role of human TEs in generating alternatively spliced transcript isoforms in cancer. To do so, we screened for the presence of TE-derived sequences co-located with alternative splice sites that are differentially used in normal versus cancer tissues. We analysed a comprehensive set of alternative splice variants characterized for 614 matched normal-tumour tissue pairs across 13 cancer types, resulting in the discovery of 4820 TE-generated alternative splice events distributed among 723 cancer-associated genes. Short interspersed nuclear elements (Alu) and long interspersed nuclear elements (L1) were found to contribute the majority of TE-generated alternative splice sites in cancer genes. A number of cancer-associated genes, including MYH11, WHSC1 and CANT1, were shown to have overexpressed TE-derived isoforms across a range of cancer types. TE-derived isoforms were also linked to cancer-specific fusion transcripts, suggesting a novel mechanism for the generation of transcriptome diversity via trans-splicing mediated by dispersed TE repeats.This article is part of a discussion meeting issue 'Crossroads between transposons and gene regulation'.