ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes
ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes
复制标题
DOI：
10.1073/pnas.0806445106
复制
发表时间：
2009-01-06
影响因子：
11.1
通讯作者：
Stolovitzky, Gustavo
中科院分区：
文献类型：
--
作者：
Margolin, Adam A.;Palomero, Teresa;Stolovitzky, Gustavo
ChIP芯片已经成为一个强大的工具，剖析转录因子和它们的目标之间的调控相互作用的复杂网络。然而，大多数ChIP芯片分析方法使用保守的方法，旨在最大限度地减少假阳性转录因子靶点。我们提出了一个模型，提高了灵敏度，从芯片上的ChIP数据检测结合事件。其应用于人类T细胞，随后进行了广泛的生物化学验证，揭示了3种致癌转录因子，NOTCH 1，MYC和HES 1，与数千个靶基因启动子结合，比传统的分析方法增加了一个数量级。NOTCH1抑制后的基因表达谱显示了在整个预测靶基因范围内的广泛功能调控，建立了占用和调控之间的更紧密联系。最后，增加的敏感性揭示了一个组合的调节程序，其中MYC cobounds几乎所有的NOTCH1结合的启动子。总的来说，这些结果表明转录调控网络的未被重视的复杂性，并强调了基因组规模的分析，以代表转录程序的根本重要性。
ChIP-on-chip has emerged as a powerful tool to dissect the complex network of regulatory interactions between transcription factors and their targets. However, most ChIP-on-chip analysis methods use conservative approaches aimed at minimizing false-positive transcription factor targets. We present a model with improved sensitivity in detecting binding events from ChIP-on-chip data. Its application to human T cells, followed by extensive biochemical validation, reveals that 3 oncogenic transcription factors, NOTCH1, MYC, and HES1, bind to several thousand target gene promoters, up to an order of magnitude increase over conventional analysis methods. Gene expression profiling upon NOTCH1 inhibition shows broad-scale functional regulation across the entire range of predicted target genes, establishing a closer link between occupancy and regulation. Finally, the increased sensitivity reveals a combinatorial regulatory program in which MYC cobinds to virtually all NOTCH1-bound promoters. Overall, these results suggest an unappreciated complexity of transcriptional regulatory networks and highlight the fundamental importance of genome-scale analysis to represent transcriptional programs.