A computational genomics approach to identify cis-regulatory modules from chromatin immunoprecipitation microarray data -: A case study using E2F1
A computational genomics approach to identify cis-regulatory modules from chromatin immunoprecipitation microarray data -: A case study using E2F1
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DOI：
10.1101/gr.5520206
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发表时间：
2006-12-01
期刊：
影响因子：
7
通讯作者：
Farnham, Peggy J.
中科院分区：
文献类型：
--
作者：
Jin, Victor X.;Rabinovich, Alina;Farnham, Peggy J.
高通量技术的进步，如ChIP芯片，以及人类和小鼠基因组序列的完成，现在允许在系统水平上分析基因调控机制。在这项研究中，我们已经开发出一种计算基因组学方法（称为ChIPModules），它开始与实验确定的结合位点，并整合位置权重矩阵构建的转录因子结合位点，比较基因组学方法，和统计学习方法，以确定转录调控模块。我们从HeLa和MCF 7细胞的ENCODE区域的ChIP芯片分析获得的E2 F1结合位点信息开始。我们的方法不仅以高特异性区分了靶标和非靶标，而且还确定了E2 F1的五个调控模块。鉴定的模块之一预测E2 F1和AP-2 α在一组靶启动子上的共定位，位点间距离< 270 bp。我们使用含有类似于14，000个人类启动子的ChIP芯片测定来测试这一预测。我们发现，E2 F1和AP- 2 α在预测的距离内与大量人类启动子结合，证明了我们基于序列的，无偏见的和通用的方案的优势。最后，我们使用我们的ChIPModules方法开发了一个数据库，其中包括数千个计算鉴定和/或实验验证的E2 F1靶启动子。
Advances in high-throughput technologies, such as ChIP-chip, and the completion of human and mouse genomic sequences now allow analysis of the mechanisms of gene regulation on a systems level. In this study, we have developed a computational genomics approach (termed ChIPModules), which begins with experimentally determined binding sites and integrates positional weight matrices constructed from transcription factor binding sites, a comparative genomics approach, and statistical learning methods to identify transcriptional regulatory modules. We began with E2F1 binding site information obtained from ChIP-chip analyses of ENCODE regions, from both HeLa and MCF7 cells. Our approach not only distinguished targets from nontargets with a high specificity, but it also identified five regulatory modules for E2F1. One of the identified modules predicted a colocalization of E2F1 and AP-2 alpha on a set of target promoters with an intersite distance of < 270 bp. We tested this prediction using ChIP-chip assays with arrays containing similar to 14,000 human promoters. We found that both E2F1 and AP- 2 alpha bind within the predicted distance to a large number of human promoters, demonstrating the strength of our sequence-based, unbiased, and universal protocol. Finally, we have used our ChIPModules approach to develop a database that includes thousands of computationally identified and/or experimentally verified E2F1 target promoters.