Hartonen Tuomo, Sahu Biswajyoti, Dave Kashyap, Kivioja Teemu, Taipale Jussi
Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Bioinformatics. 2016 Sep 1;32(17):i629-i638. doi: 10.1093/bioinformatics/btw448.
Transcription factor (TF) binding can be studied accurately in vivo with ChIP-exo and ChIP-Nexus experiments. Only fraction of TF binding mechanisms are yet fully understood and accurate knowledge of binding locations and patterns of TFs is key to understanding binding that is not explained by simple positional weight matrix models. ChIP-exo/Nexus experiments can also offer insight on the effect of single nucleotide polymorphism (SNP) at TF binding sites on expression of the target genes. This is an important mechanism of action for disease-causing SNPs at non-coding genomic regions.
We describe a peak caller PeakXus that is specifically designed to leverage the increased resolution of ChIP-exo/Nexus and developed with the aim of making as few assumptions of the data as possible to allow discoveries of novel binding patterns. We apply PeakXus to ChIP-Nexus and ChIP-exo experiments performed both in Homo sapiens and in Drosophila melanogaster cell lines. We show that PeakXus consistently finds more peaks overlapping with a TF-specific recognition sequence than published methods. As an application example we demonstrate how PeakXus can be coupled with unique molecular identifiers (UMIs) to measure the effect of a SNP overlapping with a TF binding site on the in vivo binding of the TF.
Source code of PeakXus is available at https://github.com/hartonen/PeakXus
通过ChIP-exo和ChIP-Nexus实验可以在体内准确研究转录因子（TF）结合。目前只有一部分TF结合机制得到了充分理解，准确了解TF的结合位置和模式是理解那些无法用简单位置权重矩阵模型解释的结合的关键。ChIP-exo/Nexus实验还可以深入了解TF结合位点的单核苷酸多态性（SNP）对靶基因表达的影响。这是非编码基因组区域致病SNP的一种重要作用机制。
我们描述了一种峰检测工具PeakXus，它专门设计用于利用ChIP-exo/Nexus提高的分辨率，并且在开发过程中尽可能少地对数据做假设，以便发现新的结合模式。我们将PeakXus应用于在人类和果蝇细胞系中进行的ChIP-Nexus和ChIP-exo实验。我们表明，与已发表的方法相比，PeakXus始终能发现更多与TF特异性识别序列重叠的峰。作为一个应用示例，我们展示了PeakXus如何与独特分子标识符（UMI）结合，以测量与TF结合位点重叠的SNP对TF体内结合的影响。
PeakXus的源代码可在https://github.com/hartonen/PeakXus获取。
