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Prediction and identification of transcriptional regulatory elements at the lung cancer-specific DKK1 locus

机译:肺癌特异性DKK1基因座转录调控元件的预测和鉴定

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摘要

The glycoprotein dickkopf 1 (DKK1) is highly expressed in lung cancer cell lines and tissues. Our previous study demonstrated that DKK1 promoter activity is low in lung cancer cell lines. This may be because it lacks the necessary transcriptional regulatory elements (TREs) required for higher activity levels. However, it is difficult to computationally predict functionally significant TREs, as TREs from different locations can affect large segments of distant DNA. The Encyclopedia of DNA Elements project features multiple integrated technologies and approaches for the discovery and definition of functional elements, including enhancer elements and enhancer-blocking insulators. In the present study, DNase I hypersensitive sites and histone modifications of DKK1 were investigated in the A549 lung cancer cell line using the UCSC Genome Browser. A set of cis-acting enhancer elements were identified by a dual-luciferase reporter gene assay system to increase activity of the DKK1 promoter with lung cancer specificity. To the best of our knowledge, these data provide the first insight into the role of the DKK1 locus in lung cancer, and confirm the contribution of intronic cis-acting elements to the regulation of DKK1 expression, providing a new insight into gene regulation in lung cancer, which could inform the development of targeted therapy.
机译:糖蛋白dickkopf 1(DKK1)在肺癌细胞系和组织中高度表达。我们先前的研究表明,DKK1启动子活性在肺癌细胞系中较低。这可能是因为它缺少较高活性水平所需的必需转录调控元件(TRE)。但是,很难从功能上预测重要的TRE,因为来自不同位置的TRE可能会影响远距离DNA的较大片段。 DNA元素百科全书项目采用多种集成技术和方法来发现和定义功能元件,包括增强子元件和增强子阻隔绝缘子。在本研究中,使用UCSC Genome Browser在A549肺癌细胞系中研究了DNase I超敏位点和DKK1的组蛋白修饰。通过双荧光素酶报告基因分析系统鉴定了一组顺式作用增强子,以增加DKK1启动子的活性和肺癌特异性。据我们所知,这些数据首次了解了DKK1基因座在肺癌中的作用,并证实了内含子顺式作用元件对DKK1表达调节的贡献,为对肺部基因调节提供了新的见解。癌症,这可能有助于靶向治疗的发展。

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