Improving analysis of transcription factor binding sites within ChIP-Seq data based on topological motif enrichment.
Improving analysis of transcription factor binding sites within ChIP-Seq data based on topological motif enrichment.
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DOI：
10.1186/1471-2164-15-472
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发表时间：
2014-06-13
期刊：
影响因子：
4.4
通讯作者：
Wasserman WW
中科院分区：
文献类型：
--
作者：
Worsley Hunt R;Mathelier A;Del Peso L;Wasserman WW
染色质免疫沉淀（ChIP）结合高通量测序（ChIP-Seq）技术可以揭示转录因子（TF）结合的DNA区域。ChIP-Seq区域的分析现在是基因调控研究的核心组成部分。仍然强烈需要改进ChIP-Seq数据的解释和特异性TF结合位点（TFBS）的研究的方法。我们介绍了一套方法来改善ChIP-Seq数据的解释，包括基于TFBS基序过表达分析的介导TF的推断和随后的TFBS空间分布研究。应用于ChIP-Seq数据的TFBS过度代表性分析用于检测哪些TFBS偶然出现的频率高于预期。用新的组合偏差图对过度代表性分析结果进行可视化，揭示了过度代表性分数的系统偏差。我们引入了BiasAway背景生成软件来解决这个问题。基于相对于ChIP-Seq峰的局部最大值的拓扑基序富集的启发式程序突出了可能被感兴趣的TF直接结合的峰。结果表明，平均三分之二的ChIP-Seq数据集的峰被ChIP'd TF结合;剩余峰的起源仍然未确定。额外的可视化方法允许研究TFBS间的空间关系和基序侧翼序列特性，如TBP和ZNF 143/THAP 11的案例研究所示。可以利用ChIP-Seq数据集中TFBS的拓扑特性来更好地解释调控序列。使用GC含量校正的TFBS过代表性分析，结合可视化技术和TFBS的拓扑分布分析，我们可以区分可能被TF直接结合的峰。新方法将使研究人员能够探索基因调控和TF结合。本文的在线版本（doi：10.1186/1471-2164-15-472）包含补充材料，可供授权用户使用。
Chromatin immunoprecipitation (ChIP) coupled to high-throughput sequencing (ChIP-Seq) techniques can reveal DNA regions bound by transcription factors (TF). Analysis of the ChIP-Seq regions is now a central component in gene regulation studies. The need remains strong for methods to improve the interpretation of ChIP-Seq data and the study of specific TF binding sites (TFBS). We introduce a set of methods to improve the interpretation of ChIP-Seq data, including the inference of mediating TFs based on TFBS motif over-representation analysis and the subsequent study of spatial distribution of TFBSs. TFBS over-representation analysis applied to ChIP-Seq data is used to detect which TFBSs arise more frequently than expected by chance. Visualization of over-representation analysis results with new composition-bias plots reveals systematic bias in over-representation scores. We introduce the BiasAway background generating software to resolve the problem. A heuristic procedure based on topological motif enrichment relative to the ChIP-Seq peaks’ local maximums highlights peaks likely to be directly bound by a TF of interest. The results suggest that on average two-thirds of a ChIP-Seq dataset’s peaks are bound by the ChIP’d TF; the origin of the remaining peaks remaining undetermined. Additional visualization methods allow for the study of both inter-TFBS spatial relationships and motif-flanking sequence properties, as demonstrated in case studies for TBP and ZNF143/THAP11. Topological properties of TFBS within ChIP-Seq datasets can be harnessed to better interpret regulatory sequences. Using GC content corrected TFBS over-representation analysis, combined with visualization techniques and analysis of the topological distribution of TFBS, we can distinguish peaks likely to be directly bound by a TF. The new methods will empower researchers for exploration of gene regulation and TF binding. The online version of this article (doi:10.1186/1471-2164-15-472) contains supplementary material, which is available to authorized users.
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10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
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