A signal-noise model for significance analysis of ChIP-seq with negative control
A signal-noise model for significance analysis of ChIP-seq with negative control
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DOI：
10.1093/bioinformatics/btq128
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发表时间：
2010-05-01
期刊：
影响因子：
5.8
通讯作者：
Sung, Wing-Kin
中科院分区：
文献类型：
--
作者：
Xu, Han;Handoko, Lusy;Sung, Wing-Kin
动机：ChIP-seq正在成为蛋白质-DNA相互作用和组蛋白修饰的全基因组研究的主要方法。阳离子。现有的信息学工具在提取强ChIP富集位点方面表现良好。然而，仍有两个问题有待回答：（i）ChIP-seq实验在多大程度上能够揭示弱ChIP富集位点？(ii)薄弱部位是否具有生物学意义？为了回答这些问题，有必要从背景nois.Results中识别出微弱的ChIP信号：我们提出了一个线性信号-噪声模型，其中引入了噪声率来表示ChIP库中噪声的分数。我们开发了一个迭代算法来估计噪声率使用控制库，并推导出一个库交换策略的错误发现率估计。这些方法被集成在一个通用的框架中，称为CCAT（基于控制的ChIP-seq分析工具），用于ChIP-seq的显著性分析。对H3 K4 me 3和H3 K36 me 3数据集的应用表明，CCAT预测的ChIP富集位点明显多于以前的方法。随着CCAT预测的高灵敏度，我们揭示了与强和弱H3 K4 me 3位点相关的不同染色质特征。
Motivation: ChIP-seq is becoming the main approach to the genome-wide study of protein -DNA interactions and histone modi. cations. Existing informatics tools perform well to extract strong ChIP-enriched sites. However, two questions remain to be answered: (i) to which extent is a ChIP-seq experiment able to reveal the weak ChIP-enriched sites? (ii) are the weak sites biologically meaningful? To answer these questions, it is necessary to identify the weak ChIP signals from background noise.Results: We propose a linear signal-noise model, in which a noise rate was introduced to represent the fraction of noise in a ChIP library. We developed an iterative algorithm to estimate the noise rate using a control library, and derived a library-swapping strategy for the false discovery rate estimation. These approaches were integrated in a general-purpose framework, named CCAT (Control-based ChIP-seq Analysis Tool), for the significance analysis of ChIP-seq. Applications to H3K4me3 and H3K36me3 datasets showed that CCAT predicted significantly more ChIP-enriched sites that the previous methods did. With the high sensitivity of CCAT prediction, we revealed distinct chromatin features associated to the strong and weak H3K4me3 sites.