Hallikas Outi, Palin Kimmo, Sinjushina Natalia, Rautiainen Reetta, Partanen Juha, Ukkonen Esko, Taipale Jussi
Molecular and Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, Finland.
Cell. 2006 Jan 13;124(1):47-59. doi: 10.1016/j.cell.2005.10.042.
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.
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TF结合位点组装形成组织特异性增强子元件的组合密码组成。我们使用一种新型高通量方法，确定了GLIs 1 - 3、Tcf4和c - Ets1的DNA结合特异性，这些转录因子介导对刺猬信号通路（Hh）、Wnt信号通路和Ras/MAPK信号通路的转录反应。为了在基因组规模上鉴定受这些信号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可用于鉴定Hh和Wnt靶基因，并根据基因表达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，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重要意义。
