Systems-epigenomics inference of transcription factor activity implicates aryl-hydrocarbon-receptor inactivation as a key event in lung cancer development.
Systems-epigenomics inference of transcription factor activity implicates aryl-hydrocarbon-receptor inactivation as a key event in lung cancer development.
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转录因子活性的系统表观基因组学推断表明芳基烃受体失活是肺癌发展的关键事件。
DOI：
10.1186/s13059-017-1366-0
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发表时间：
2017-12-20
期刊：
影响因子：
12.3
通讯作者：
Teschendorff AE
中科院分区：
文献类型：
--
作者：
Chen Y;Widschwendter M;Teschendorff AE
在正常和前驱肺癌细胞中，与吸烟相关的各种分子变化已有报道，但它们在肺癌病因中的作用尚不清楚。一个突出的例子是芳烃受体抑制物(AHRR)基因的低甲基化，这种现象在吸烟者的血液和鳞状上皮细胞中观察到，但在肺癌中没有观察到。使用一种名为SEPIRA的新系统表观基因组学算法，该算法利用大型RNA测序表达简编的能力，从信使RNA表达或DNA甲基化(DNaM)谱推断调节活性，我们推断肺特异转录因子(TF)在肺癌发生中的结合活性图景。我们发现，在肺癌和前驱肺癌病变中，肺特异的转录因子优先失活，并进一步证明，仅使用dNaM数据就可以得出这些结果。我们确定了在前体细胞中失活的转录因子亚群。在这些调节因子中，我们确定了AHR，这是一种芳香烃受体，它控制着肺上皮细胞的健康免疫反应，其抑制物AHRR最近被认为与吸烟介导的肺癌有关。此外，我们鉴定了FOXJ1，一种能促进呼吸道纤毛生长和有效清除致癌物的肺上皮细胞的转移因子。我们确定了转铁蛋白，如AHR，它们在肺癌的早期阶段失活，与AHRR低甲基化不同，它们在肺癌本身也是失活的。新的系统-表观基因组学算法SEPIRA将作为推断调控活动的一种手段，对更广泛的表观基因组关联研究社区有用。本文的在线版本(doi：10.1186/s13059-017-1366-0)包含补充材料，授权用户可以使用。
Diverse molecular alterations associated with smoking in normal and precursor lung cancer cells have been reported, yet their role in lung cancer etiology remains unclear. A prominent example is hypomethylation of the aryl hydrocarbon-receptor repressor (AHRR) locus, which is observed in blood and squamous epithelial cells of smokers, but not in lung cancer. Using a novel systems-epigenomics algorithm, called SEPIRA, which leverages the power of a large RNA-sequencing expression compendium to infer regulatory activity from messenger RNA expression or DNA methylation (DNAm) profiles, we infer the landscape of binding activity of lung-specific transcription factors (TFs) in lung carcinogenesis. We show that lung-specific TFs become preferentially inactivated in lung cancer and precursor lung cancer lesions and further demonstrate that these results can be derived using only DNAm data. We identify subsets of TFs which become inactivated in precursor cells. Among these regulatory factors, we identify AHR, the aryl hydrocarbon-receptor which controls a healthy immune response in the lung epithelium and whose repressor, AHRR, has recently been implicated in smoking-mediated lung cancer. In addition, we identify FOXJ1, a TF which promotes growth of airway cilia and effective clearance of the lung airway epithelium from carcinogens. We identify TFs, such as AHR, which become inactivated in the earliest stages of lung cancer and which, unlike AHRR hypomethylation, are also inactivated in lung cancer itself. The novel systems-epigenomics algorithm SEPIRA will be useful to the wider epigenome-wide association study community as a means of inferring regulatory activity. The online version of this article (doi:10.1186/s13059-017-1366-0) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
Gao X;Zhang Y;Breitling LP;Brenner H
通讯作者：
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DOI：
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影响因子：
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