Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity
Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity
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DOI：
10.1016/j.cell.2005.10.042
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发表时间：
2006-01-13
期刊：
影响因子：
64.5
通讯作者：
Taipale, J
中科院分区：
文献类型：
--
作者：
Hallikas, O;Palin, K;Taipale, J
理解人类基因表达的调控需要了解“第二遗传密码”，它由转录因子（TFs）的结合特异性以及转录因子结合位点组合形成组织特异性增强子元件的组合密码组成。我们利用一种新型的高通量方法，确定了GLI1 - 3、Tcf4和c - Ets1的DNA结合特异性，这些因子介导对刺猬（Hh）、Wnt和Ras/MAPK信号通路的转录反应。为了在基因组水平上识别受这些通路调控的哺乳动物增强子元件，我们开发了一种计算工具，增强子元件定位器（EEL）。我们表明EEL可用于识别Hh和Wnt靶基因，并根据基因表达的变化预测激活的转录因子。在转基因小鼠胚胎中得到验证的预测结果揭示了小鼠c - Myc和N - Myc基因中存在多个组织特异性增强子，这对器官特异性生长控制和癌基因的肿瘤类型特异性具有影响。
Understanding the regulation of human gene expression requires knowledge of the "second genetic code," which consists of the binding specificities of transcription factors (TFs) and the combinatorial code by which TF binding sites are assembled to form tissue-specific enhancer elements. Using a novel high-throughput method, we determined the DNA binding specificities of GLIs 1-3, Tcf4, and c-Ets1, which mediate transcriptional responses to the Hedgehog (Hh), Wnt, and Ras/MAPK signaling pathways. To identify mammalian enhancer elements regulated by these pathways on a genomic scale, we developed a computational tool, enhancer element locator (EEL). We show that EEL can be used to identify Hh and Wnt target genes and to predict activated TFs based on changes in gene expression. Predictions validated in transgenic mouse embryos revealed the presence of multiple tissue-specific enhancers in mouse c-Myc and N-Myc genes, which has implications for organ-specific growth control and tumor-type specificity of oncogenes.