An integrated model of multiple-condition ChIP-Seq data reveals predeterminants of Cdx2 binding.
An integrated model of multiple-condition ChIP-Seq data reveals predeterminants of Cdx2 binding.
复制标题
DOI：
10.1371/journal.pcbi.1003501
复制
发表时间：
2014-03
影响因子：
4.3
通讯作者：
Gifford DK
中科院分区：
文献类型：
--
作者：
Mahony S;Edwards MD;Mazzoni EO;Sherwood RI;Kakumanu A;Morrison CA;Wichterle H;Gifford DK
调节蛋白可以在各种细胞类型或条件下结合到不同的基因组靶标组。为了可靠地表征这种条件特异性调控结合，我们引入了MultiGPS，这是一种用于分析多个相关ChIP-seq实验的集成机器学习方法。MultiGPS基于广义期望最大化框架，该框架在多个实验中共享信息以进行绑定事件发现。我们证明，我们的框架能够同时建模稀疏条件特异性结合的变化，序列依赖性，和复制特定的噪声源。MultiGPS鼓励在多条件ChIP-seq数据集中报告的结合事件位置的一致性，并提供每个事件的ChIP富集水平的准确估计。因此，MultiGPS的多实验建模方法为检测实验条件下的差异结合富集提供了可靠的平台。我们展示了MultiGPS的优势与Cdx 2结合在三个不同的发展背景下的分析。通过准确地表征条件特异性Cdx 2结合，MultiGPS能够对Cdx 2位点选择性的机制基础进行新的洞察。具体而言，条件特异性Cdx 2位点的特点是MultiGPS与预先存在的基因组背景高度相关，这表明这些网站是预先确定的细胞特异性的监管架构。然而，MultiGPS定义的条件无关的网站没有预测预先存在的监管信号，这表明Cdx 2可以结合到一个子集的位置，无论基因组环境。本文的摘要出现在4月2日至5日的RECOMB 2014会议记录中。许多调节其他基因活性的蛋白质是通过在特定的结合位点附着在基因组上来实现的。给定的调节蛋白将结合的位置，以及在单个位置的这种结合的强度或频率，可以根据细胞类型而变化。我们可以使用一种称为ChIP-seq的实验方法来分析蛋白质在特定细胞类型中结合的位置，然后对数据进行计算解释。然而，由于实验数据通常是有噪声的，通常很难比较多个实验中ChIP-seq数据的计算分析，以了解不同细胞类型中可能发生的结合差异。在本文中，我们提出了一种名为MultiGPS的新计算方法，用于以综合方式同时分析多个相关的ChIP-seq实验。通过以适当的方式分析所有数据，我们可以更准确地了解蛋白质与基因组结合的位置，并且我们可以更容易和可靠地检测不同细胞类型蛋白质结合的差异。我们展示了MultiGPS软件，使用三种不同发育细胞类型中调节蛋白Cdx 2的新分析。
Regulatory proteins can bind to different sets of genomic targets in various cell types or conditions. To reliably characterize such condition-specific regulatory binding we introduce MultiGPS, an integrated machine learning approach for the analysis of multiple related ChIP-seq experiments. MultiGPS is based on a generalized Expectation Maximization framework that shares information across multiple experiments for binding event discovery. We demonstrate that our framework enables the simultaneous modeling of sparse condition-specific binding changes, sequence dependence, and replicate-specific noise sources. MultiGPS encourages consistency in reported binding event locations across multiple-condition ChIP-seq datasets and provides accurate estimation of ChIP enrichment levels at each event. MultiGPS's multi-experiment modeling approach thus provides a reliable platform for detecting differential binding enrichment across experimental conditions. We demonstrate the advantages of MultiGPS with an analysis of Cdx2 binding in three distinct developmental contexts. By accurately characterizing condition-specific Cdx2 binding, MultiGPS enables novel insight into the mechanistic basis of Cdx2 site selectivity. Specifically, the condition-specific Cdx2 sites characterized by MultiGPS are highly associated with pre-existing genomic context, suggesting that such sites are pre-determined by cell-specific regulatory architecture. However, MultiGPS-defined condition-independent sites are not predicted by pre-existing regulatory signals, suggesting that Cdx2 can bind to a subset of locations regardless of genomic environment. A summary of this paper appears in the proceedings of the RECOMB 2014 conference, April 2–5. Many proteins that regulate the activity of other genes do so by attaching to the genome at specific binding sites. The locations that a given regulatory protein will bind, and the strength or frequency of such binding at an individual location, can vary depending on the cell type. We can profile the locations that a protein binds in a particular cell type using an experimental method called ChIP-seq, followed by computational interpretation of the data. However, since the experimental data are typically noisy, it is often difficult to compare the computational analyses of ChIP-seq data across multiple experiments in order to understand any differences in binding that may occur in different cell types. In this paper, we present a new computational method named MultiGPS for simultaneously analyzing multiple related ChIP-seq experiments in an integrated manner. By analyzing all the data together in an appropriate way, we can gain a more accurate picture of where the profiled protein is binding to the genome, and we can more easily and reliably detect differences in protein binding across cell types. We demonstrate the MultiGPS software using a new analysis of the regulatory protein Cdx2 in three different developmental cell types.
登录
查看更多内容
DOI：
10.1073/pnas.1204398110
发表时间：
2013-04-23
影响因子：
11.1
作者：
Ji, Hongkai;Li, Xia;Ning, Yang
通讯作者：
Ning, Yang
影响因子：
23.9
作者：
Heng, Jian-Chien Dominic;Feng, Bo;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui
DOI：
10.1109/34.990138
发表时间：
2002-03-01
影响因子：
23.6
作者：
Figueiredo, MAT;Jain, AK
通讯作者：
Jain, AK
影响因子：
30.8
作者：
John S;Sabo PJ;Thurman RE;Sung MH;Biddie SC;Johnson TA;Hager GL;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA
影响因子：
4.3
作者：
Guo Y;Mahony S;Gifford DK
通讯作者：
Gifford DK