Comprehensive annotation of bidirectional promoters identifies co-regulation among breast and ovarian cancer genes.
Comprehensive annotation of bidirectional promoters identifies co-regulation among breast and ovarian cancer genes.
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双向启动子的全面注释确定乳腺癌和卵巢癌基因之间的共同调节。
DOI：
10.1371/journal.pcbi.0030072
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发表时间：
2007-04-20
影响因子：
4.3
通讯作者：
Elnitski, Laura
中科院分区：
文献类型：
--
作者：
Yang, Mary Q.;Koehly, Laura M.;Elnitski, Laura
“双向基因对”包括两个相邻的基因，它们的转录起始点是相邻的，并且相互引导远离。参与其中的调控区域被称为“双向启动子”。这些启动子通常与在DNA修复中起作用的基因有关，有可能参与癌症的发展。以前还没有研究过这些基因对与癌症之间的联系。利用剪接表达序列标签(EST)数据库，我们确定了双向启动子控制下最完整的人类转录本集合。对拼接的EST数据的严格筛选发现了新的双向启动子，其中许多起到了替代启动子或受调控的小说转录本的作用。此外，我们发现在与体细胞癌有关的基因中双向启动子的含量非常显著地丰富，包括与乳腺癌和卵巢癌有关的大量基因。在人类基因组中反复使用这种启动子结构表明，它可以调节基因组之间的共表达模式。使用来自79个人类组织的微阵列表达数据，我们验证了双向启动子控制的基因之间的调控网络。这些启动子的子集包含相似的转录因子结合位点组合，包括ERBB2、FANCD2和BRCA2中进化保守的ETS因子结合位点。解释共表达网络中涉及的基因的调控，特别是那些涉及癌症的基因，将是朝着确定可能导致疾病的分子事件迈出的重要一步。启动子是控制基因转录的调节区。一类特殊的启动子，称为双向启动子，调节两个基因的表达，而不是一个。这些启动子位于两个相邻基因之间，这两个基因的转录起始点实际在1,000个碱基对以内，并且方向相反。在基因组中反复发现双向启动子，表明这种调控结构具有重要的生物学意义。我们开发了一种算法，使用从转录序列的全面列表中获得的数据来映射双向启动子，该列表被称为表达序列标签，或EST。这种方法将以前表征的双向启动子的数量提高了300%。新数据包括双向启动子，这些启动子调控与体细胞癌有关的基因的表达。例如，10个公认的与乳腺癌和卵巢癌有关的基因被确定为具有双向启动子。其中三个基因通过在其双向启动子内具有相同转录因子结合位点的重复拷贝而进一步相关。这些结合位点在物种之间是保守的，提供了更多的证据表明它们在功能上是重要的。在这个例子中，类似的调控结构被用来控制与癌症有关的基因，说明了如何从全面的双向启动子集合中挖掘数据。在这篇手稿中，我们展示了许多癌症基因受双向启动子调控的统计证据。这些启动子将成为研究基因调控在肿瘤发展中的作用的有价值的数据集。
A “bidirectional gene pair” comprises two adjacent genes whose transcription start sites are neighboring and directed away from each other. The intervening regulatory region is called a “bidirectional promoter.” These promoters are often associated with genes that function in DNA repair, with the potential to participate in the development of cancer. No connection between these gene pairs and cancer has been previously investigated. Using the database of spliced-expressed sequence tags (ESTs), we identified the most complete collection of human transcripts under the control of bidirectional promoters. A rigorous screen of the spliced EST data identified new bidirectional promoters, many of which functioned as alternative promoters or regulated novel transcripts. Additionally, we show a highly significant enrichment of bidirectional promoters in genes implicated in somatic cancer, including a substantial number of genes implicated in breast and ovarian cancers. The repeated use of this promoter structure in the human genome suggests it could regulate co-expression patterns among groups of genes. Using microarray expression data from 79 human tissues, we verify regulatory networks among genes controlled by bidirectional promoters. Subsets of these promoters contain similar combinations of transcription factor binding sites, including evolutionarily conserved ETS factor binding sites in ERBB2, FANCD2, and BRCA2. Interpreting the regulation of genes involved in co-expression networks, especially those involved in cancer, will be an important step toward defining molecular events that may contribute to disease. Promoters are regulatory regions that control transcription of genes. A special class of promoters, known as bidirectional promoters, regulates expression of two genes instead of one. These promoters are situated between two adjacent genes whose transcription start sites are physically within 1,000 bp and oriented in opposite directions. Bidirectional promoters are found repeatedly in the genome, suggesting an important biological significance for this regulatory configuration. We developed an algorithm to map bidirectional promoters using data from a comprehensive list of transcribed sequences known as expressed sequence tags, or ESTs. This approach improved the number of previously characterized bidirectional promoters by 300%. Included in the new data are bidirectional promoters that regulate expression of genes implicated in somatic cancers. For instance, ten well-recognized genes implicated in breast and ovarian cancers were identified as having bidirectional promoters. Three of the genes are further related by having duplicate copies of the same binding site for a transcription factor within their bidirectional promoters. These binding sites are conserved among species, providing greater evidence that they are functionally important. This example, in which similar regulatory structures are used to control genes involved in cancer, illustrates how data can be mined from the comprehensive set of bidirectional promoters. Within this manuscript, we show statistical evidence that many cancer genes are regulated by bidirectional promoters. These promoters will be a valuable dataset for studying the role of gene regulation in tumor development.
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影响因子：
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