Discriminative prediction of mammalian enhancers from DNA sequence
Discriminative prediction of mammalian enhancers from DNA sequence
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DOI：
10.1101/gr.121905.111
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发表时间：
2011-12-01
期刊：
影响因子：
7
通讯作者：
Beer, Michael A.
中科院分区：
文献类型：
--
作者：
Lee, Dongwon;Karchin, Rachel;Beer, Michael A.
准确预测整个基因组中的调控序列和增强子是一个重要但困难的问题，特别是在大型脊椎动物基因组中。随着芯片序列技术的出现，对全基因组EP300/CREBBP结合区的实验检测为开发调控序列的预测工具和研究其序列性质提供了一个强大的平台。在这里，我们开发了一个支持向量机(SVM)框架，它可以仅使用基因组序列和一组无偏的一般序列特征来准确识别EP300结合的增强子。此外，我们发现，支持向量机分类器识别的预测序列特征揭示了富含增强剂的生物相关序列元素，但我们也识别了其他明显缺乏增强剂的特征。预测序列特征在进化上是保守的，并在空间上聚集，为它们的功能意义提供了进一步的支持。虽然我们的支持向量机是基于实验数据进行训练的，但我们也预测了新的增强子，并表明这些假定的增强子在小鼠大脑中显著富含ChIP-Seq信号和DNase I超敏信号，并位于相关基因附近。最后，我们给出了使用我们的支持向量机在其他EP300/CREBBP数据集之间进行比较的结果，并发现了在不同类别的增强子中丰富和/或耗尽的序列元件。这些序列特征中的许多在指定组织特异性或发育阶段特异性增强子活性方面发挥作用，但我们的结果表明，一些特征以一般或组织无关的方式起作用。除了为后续的实验研究提供增强子靶标的高置信度列表外，这些结果还有助于我们理解脊椎动物增强子的一般序列结构。
Accurately predicting regulatory sequences and enhancers in entire genomes is an important but difficult problem, especially in large vertebrate genomes. With the advent of ChIP-seq technology, experimental detection of genome-wide EP300/CREBBP bound regions provides a powerful platform to develop predictive tools for regulatory sequences and to study their sequence properties. Here, we develop a support vector machine (SVM) framework which can accurately identify EP300-bound enhancers using only genomic sequence and an unbiased set of general sequence features. Moreover, we find that the predictive sequence features identified by the SVM classifier reveal biologically relevant sequence elements enriched in the enhancers, but we also identify other features that are significantly depleted in enhancers. The predictive sequence features are evolutionarily conserved and spatially clustered, providing further support of their functional significance. Although our SVM is trained on experimental data, we also predict novel enhancers and show that these putative enhancers are significantly enriched in both ChIP-seq signal and DNase I hypersensitivity signal in the mouse brain and are located near relevant genes. Finally, we present results of comparisons between other EP300/CREBBP data sets using our SVM and uncover sequence elements enriched and/or depleted in the different classes of enhancers. Many of these sequence features play a role in specifying tissue-specific or developmental-stage-specific enhancer activity, but our results indicate that some features operate in a general or tissue-independent manner. In addition to providing a high confidence list of enhancer targets for subsequent experimental investigation, these results contribute to our understanding of the general sequence structure of vertebrate enhancers.