The ets-related transcription factor GABP directs bidirectional transcription.
The ets-related transcription factor GABP directs bidirectional transcription.
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DOI：
10.1371/journal.pgen.0030208
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发表时间：
2007-11
期刊：
影响因子：
4.5
通讯作者：
Myers RM
中科院分区：
文献类型：
--
作者：
Collins PJ;Kobayashi Y;Nguyen L;Trinklein ND;Myers RM
人类基因组中约有10％的基因分布，使它们的转录起始位点位于相对的链上小于1 kb。这些发散的基因对具有单个基因间DNA，在某些情况下似乎具有调节元件，但是尚不清楚这些区域是功能性双向启动子还是两个重叠的启动子。最近的一项研究表明，发散的启动子富含一小组转录因子的共有结合序列，包括无处不在的ETS-元素转录因子GA结合蛋白（GABP）。在这里，我们表明，GABP与至少一种细胞类型中的80％以上的发散启动子结合。此外，我们证明了GABP结合是相关的，并且与荧光素酶转染测定法中的双向转录活性相关。此外，我们发现在67％的情况下，通常仅在一个方向上起作用的一组启动子中，将严格的GABP站点添加到一组启动子中，会显着增加相反方向的活性。我们的发现表明，GABP调节大多数发散启动子，并表明双向转录活性是通过在发散和非发散启动子处通过GABP结合和反式激活来介导的。
对人基因组中基因位置的调查表明，大于10％的基因数量令人惊讶，在相反的链上彼此之间具有转录起始位点。这些不同的基因对，有时称为双向基因，在细菌和酵母等生物中很常见，但是尚不清楚为什么这种排列存在于大型的哺乳动物基因组中。最近，很明显，这些不同的基因的启动子受转录因子的一部分调节，我们专注于其中一种GA结合蛋白（GABP）。我们发现它调节了大量的人类基因，包括大多数发散基因，并且其结合与双向转录活性相关，与之相关，并且足以相关。尽管显然GABP是发散基因的主要调节因子，这些基因对细胞的功能和存活至关重要，但这些数据还提出了GABP作为转录因子的新作用。例如，GABP促进双向转录的能力可能被证明在生物学上与生成许多在蛋白质编码基因之外观察到的转录本相关。
Approximately 10% of genes in the human genome are distributed such that their transcription start sites are located less than 1 kb apart on opposite strands. These divergent gene pairs have a single intergenic segment of DNA, which in some cases appears to share regulatory elements, but it is unclear whether these regions represent functional bidirectional promoters or two overlapping promoters. A recent study showed that divergent promoters are enriched for consensus binding sequences of a small group of transcription factors, including the ubiquitous ets-family transcription factor GA-binding protein (GABP). Here we show that GABP binds to more than 80% of divergent promoters in at least one cell type. Furthermore, we demonstrate that GABP binding is correlated and associated with bidirectional transcriptional activity in a luciferase transfection assay. In addition, we find that the addition of a strict consensus GABP site into a set of promoters that normally function in only one direction significantly increases activity in the opposite direction in 67% of cases. Our findings demonstrate that GABP regulates the majority of divergent promoters and suggest that bidirectional transcriptional activity is mediated through GABP binding and transactivation at both divergent and nondivergent promoters. Surveys of the locations of genes in the human genome have revealed that a surprising number of genes, greater than 10%, have transcription start sites within 1 kb of one another on opposite strands. These divergent gene pairs, sometimes referred to as bidirectional genes, are common in organisms such as bacteria and yeast, but it is unknown why such an arrangement exists in large, mammalian genomes. Recently, it has become apparent that the promoters of these divergent genes are regulated by a subset of transcription factors, and we have focused on one of these, GA-binding protein (GABP). We find that it regulates a large number of human genes, including the majority of divergent genes, and that its binding is associated with, correlated with, and sufficient for bidirectional transcriptional activity. Although clearly GABP is a major regulator of divergent genes, which carry out a variety of roles critical for the function and survival of the cell, these data also propose novel roles for GABP as a transcription factor. For example, the ability of GABP to promote bidirectional transcription may prove to be biologically relevant in generating many of the transcripts that have been observed outside of protein coding genes.
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