Genome-wide prediction of cis-acting RNA elements regulating tissue-specific pre-mRNA alternative splicing.
Genome-wide prediction of cis-acting RNA elements regulating tissue-specific pre-mRNA alternative splicing.
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DOI：
10.1186/1471-2164-10-s1-s4
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发表时间：
2009-07-07
期刊：
影响因子：
4.4
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Wang X;Wang K;Radovich M;Wang Y;Wang G;Feng W;Sanford JR;Liu Y
人类基因在不同的组织中经历不同的前mRNA剪接模式。这种变异主要由结合在外显子和内含子顺式作用RNA元件（CAE）上的反式作用因子调节。在这里，我们报告了一种计算方法，机械地确定顺式作用RNA元件，有助于组织特异性选择性剪接模式。该方法是我们以前的模型SplicingModeler的扩展，该模型预测了导致两种组织之间剪接差异的重要CAE。在这项研究中，我们引入了组织特异性功能水平估计步骤，它允许评估预测的涉及两个以上组织的CAEs的调节功能。使用公开可用的AffysseGenechip ® Human Exon Array数据集，我们的方法在11种人体组织中鉴定了652个顺式作用RNA元件（CAE）。大约三分之一的预测的CAEs可以映射到已知的RBP（RNA结合蛋白）结合位点或与其他预测的外显子剪接调控子数据库匹配。有趣的是，绝大多数预测的CAE都在内含子调控区。一个值得注意的例外是，许多外显子元件被发现调节小脑和睾丸之间的选择性剪接。发现大多数鉴定的元件有助于两种组织之间的选择性剪接，而一些元件在多种组织中是重要的。这表明，全基因组可变剪接模式的组织特异性顺式作用元件和“一般元件”的功能活动是重要的，但不同的多个组织的组合进行调节。在这项研究中，我们提出了一个基于模型的计算方法，以确定潜在的顺式作用RNA元件，考虑外显子剪接的变化作为多个顺式作用调节剂的组合效应。这种方法提供了一种新的评估顺式作用RNA元件的功能水平，通过估计其组织特异性功能的各种组织。
Human genes undergo various patterns of pre-mRNA splicing across different tissues. Such variation is primarily regulated by trans-acting factors that bind on exonic and intronic cis-acting RNA elements (CAEs). Here we report a computational method to mechanistically identify cis-acting RNA elements that contribute to the tissue-specific alternative splicing pattern. This method is an extension of our previous model, SplicingModeler, which predicts the significant CAEs that contribute to the splicing differences between two tissues. In this study, we introduce tissue-specific functional levels estimation step, which allows evaluating regulatory functions of predicted CAEs that are involved in more than two tissues. Using a publicly available Affymetrix Genechip® Human Exon Array dataset, our method identifies 652 cis-acting RNA elements (CAEs) across 11 human tissues. About one third of predicted CAEs can be mapped to the known RBP (RNA binding protein) binding sites or match with other predicted exonic splicing regulator databases. Interestingly, the vast majority of predicted CAEs are in intronic regulatory regions. A noticeable exception is that many exonic elements are found to regulate the alternative splicing between cerebellum and testes. Most identified elements are found to contribute to the alternative splicing between two tissues, while some are important in multiple tissues. This suggests that genome-wide alternative splicing patterns are regulated by a combination of tissue-specific cis-acting elements and "general elements" whose functional activities are important but differ across multiple tissues. In this study, we present a model-based computational approach to identify potential cis-acting RNA elements by considering the exon splicing variation as the combinatorial effects of multiple cis-acting regulators. This methodology provides a novel evaluation on the functional levels of cis-acting RNA elements by estimating their tissue-specific functions on various tissues.