Deciphering the transcriptional regulation of microRNA genes in humans with ACTLocater.
Deciphering the transcriptional regulation of microRNA genes in humans with ACTLocater.
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DOI：
10.1093/nar/gks821
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发表时间：
2013-01-07
影响因子：
14.9
通讯作者：
Qu LH
中科院分区：
文献类型：
--
作者：
Xiao ZD;Diao LT;Yang JH;Xu H;Huang MB;Deng YJ;Zhou H;Qu LH
了解microRNA（miRNAs）的转录调控对于确定它们在信号级联中发挥的特定作用非常重要。然而，精确鉴定协调miRNA表达的转录因子结合位点（TFBS）仍然是一个挑战。通过结合ENCODE项目发布的12种细胞类型的可访问染色质序列，我们发现这种整合序列的显著部分（约80%），进化保守的和独立转录的人类miRNA基因上游区域，在细胞类型中被保留。因此，我们开发了一种计算方法，可重复和保守的TFBS定位器（ACTLocater），结合这种染色质特征和进化保守性来识别与人类miRNA基因相关的TFBS。ACTLocater实现了高阳性预测值，如FOXA 1预测的实验验证以及将其对一些其他转录因子（TF）的预测与经验ChIP-seq数据的比较所揭示的。最值得注意的是，ACTLocater是广泛适用的，如成功预测TF→miRNA相互作用的细胞类型，其染色质可及性概况没有纳入。通过将ACTLocater应用于具有特征性结合特异性的TF，我们编制了一个新的推定TF→miRNA相互作用的库，并将其显示在ACTViewer中，为未来研究阐明人类miRNA转录的调控机制提供了有希望的基础。
Understanding the transcriptional regulation of microRNAs (miRNAs) is extremely important for determining the specific roles they play in signaling cascades. However, precise identification of transcription factor binding sites (TFBSs) orchestrating the expressions of miRNAs remains a challenge. By combining accessible chromatin sequences of 12 cell types released by the ENCODE Project, we found that a significant fraction (∼80%) of such integrated sequences, evolutionary conserved and in regions upstream of human miRNA genes that are independently transcribed, were preserved across cell types. Accordingly, we developed a computational method, Accessible and Conserved TFBSs Locater (ACTLocater), incorporating this chromatin feature and evolutionary conservation to identify the TFBSs associated with human miRNA genes. ACTLocater achieved high positive predictive values, as revealed by the experimental validation of FOXA1 predictions and by the comparison of its predictions of some other transcription factors (TFs) to empirical ChIP-seq data. Most notably, ACTLocater was widely applicable as indicated by the successful prediction of TF→miRNA interactions in cell types whose chromatin accessibility profiles were not incorporated. By applying ACTLocater to TFs with characterized binding specificities, we compiled a novel repository of putative TF→miRNA interactions and displayed it in ACTViewer, providing a promising foundation for future investigations to elucidate the regulatory mechanisms of miRNA transcription in humans.
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