Intronic Alus influence alternative splicing.
Intronic Alus influence alternative splicing.
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DOI：
10.1371/journal.pgen.1000204
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发表时间：
2008-09-26
期刊：
影响因子：
4.5
通讯作者：
Ast G
中科院分区：
文献类型：
--
作者：
Lev-Maor G;Ram O;Kim E;Sela N;Goren A;Levanon EY;Ast G
对人类转录组的检查显示，RNA编辑水平高于迄今为止测试的任何其他生物。这表明在人类转录组内广泛的双链RNA（dsRNA）形成。大多数编辑位点位于灵长类特有的称为Alu的逆转录元件中。在内含子序列中发现了大部分Alus，这意味着mRNA前体中广泛的Alu dsRNA形成。然而，这些内含子Alus对侧翼外显子剪接的影响在很大程度上是未知的。在这里，我们表明，更多的Alus侧翼选择性剪接的外显子比组成性剪接的，这是特别值得注意的那些外显子，已经改变了他们的剪接模式，从组成的替代在人类进化过程中。这意味着Alu的插入可能会改变侧翼外显子的剪接模式。事实上，我们通过实验证明，两个Alu元件以相反的方向插入内含子中进行碱基配对，如RNA编辑所示，并影响下游外显子的剪接模式，将其从组成型转变为替代型。我们的研究结果表明内含子Alus在影响侧翼外显子剪接中的重要性，进一步强调了Alus在人类转录组形成中的作用。人类基因组中有超过100万个灵长类特异性逆转录转座元件（称为Alu）。大部分Alu元件位于内含子序列内。人类转录组经历了广泛的RNA编辑（A-to-I），比任何其他测试的生物体都要高。RNA编辑需要形成双链RNA结构才能发生。人类转录组中超过90%的编辑位点位于Alu序列中。因此，高水平的RNA编辑表明由内含子的Al-Alu碱基配对驱动的mRNA前体中广泛的二级结构形成。剪接是一种分子机制，其中内含子从mRNA前体中去除，外显子连接以形成成熟的mRNA。在这里，我们表明，插入到内含子中的Alu可以影响侧翼外显子的剪接。我们的实验表明，两个Alu元素，插入到同一内含子中的相反方向进行碱基配对，并因此转移剪接模式的下游外显子从组成性包含在所有成熟的mRNA分子的选择性跳跃。这强调了Alu元件对灵长类特异性转录组进化的影响，因为这些事件可以产生可能获得新功能的新亚型。
Examination of the human transcriptome reveals higher levels of RNA editing than in any other organism tested to date. This is indicative of extensive double-stranded RNA (dsRNA) formation within the human transcriptome. Most of the editing sites are located in the primate-specific retrotransposed element called Alu. A large fraction of Alus are found in intronic sequences, implying extensive Alu-Alu dsRNA formation in mRNA precursors. Yet, the effect of these intronic Alus on splicing of the flanking exons is largely unknown. Here, we show that more Alus flank alternatively spliced exons than constitutively spliced ones; this is especially notable for those exons that have changed their mode of splicing from constitutive to alternative during human evolution. This implies that Alu insertions may change the mode of splicing of the flanking exons. Indeed, we demonstrate experimentally that two Alu elements that were inserted into an intron in opposite orientation undergo base-pairing, as evident by RNA editing, and affect the splicing patterns of a downstream exon, shifting it from constitutive to alternative. Our results indicate the importance of intronic Alus in influencing the splicing of flanking exons, further emphasizing the role of Alus in shaping of the human transcriptome. The human genome is crowded with over one million copies of primate-specific retrotransposed elements, termed Alu. A large fraction of Alu elements are located within intronic sequences. The human transcriptome undergoes extensive RNA editing (A-to-I), to higher levels than any other tested organism. RNA editing requires the formation of a double-stranded RNA structure in order to occur. Over 90% of the editing sites in the human transcriptome are found within Alu sequences. Thus, the high level of RNA editing is indicative of extensive secondary structure formation in mRNA precursors driven by intronic Alu-Alu base pairing. Splicing is a molecular mechanism in which introns are removed from an mRNA precursor and exons are ligated to form a mature mRNA. Here, we show that Alu insertions into introns can affect the splicing of the flanking exons. We experimentally demonstrate that two Alu elements that were inserted into the same intron in opposite orientation undergo base-pairing, and consequently shift the splicing pattern of the downstream exon from constitutive inclusion in all mature mRNA molecules to alternative skipping. This emphasizes the impact of Alu elements on the primate-specific transcriptome evolution, as such events can generate new isoforms that might acquire novel functions.
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