Lin Jane M, Collins Patrick J, Trinklein Nathan D, Fu Yutao, Xi Hualin, Myers Richard M, Weng Zhiping
Department of Biomedical Engineering, Boston University, Boston, Massachusetts, 02215, USA.
Genome Res. 2007 Jun;17(6):818-27. doi: 10.1101/gr.5623407.
Bidirectional promoters have received considerable attention because of their ability to regulate two downstream genes (divergent genes). They are also highly abundant, directing the transcription of approximately 11% of genes in the human genome. We categorized the presence of DNA sequence motifs, binding of transcription factors, and modified histones as overrepresented, shared, or underrepresented in bidirectional promoters with respect to unidirectional promoters. We found that a small set of motifs, including GABPA, MYC, E2F1, E2F4, NRF-1, CCAAT, YY1, and ACTACAnnTCC are overrepresented in bidirectional promoters, while the majority (73%) of known vertebrate motifs are underrepresented. We performed chromatin-immunoprecipitation (ChIP), followed by quantitative PCR for GABPA, on 118 regions in the human genome and showed that it binds to bidirectional promoters more frequently than unidirectional promoters, and its position-specific scoring matrix is highly predictive of binding. Signatures of active transcription, such as occupancy of RNA polymerase II and the modified histones H3K4me2, H3K4me3, and H3ac, are overrepresented in regions around bidirectional promoters, suggesting that a higher fraction of divergent genes are transcribed in a given cell than the fraction of other genes. Accordingly, analysis of whole-genome microarray data indicates that 68% of divergent genes are transcribed compared with 44% of all human genes. By combining the analysis of publicly available ENCODE data and a detailed study of GABPA, we survey bidirectional promoters with breadth and depth, leading to biological insights concerning their motif composition and bidirectional regulatory mode.
双向启动子因其调控两个下游基因（反向基因）的能力而受到了广泛关注。它们也极为丰富，指导着人类基因组中约11%的基因转录。我们将DNA序列基序的存在、转录因子的结合以及修饰组蛋白在双向启动子中相对于单向启动子的情况分类为过度富集、共享或低富集。我们发现，一小部分基序，包括GABPA、MYC、E2F1、E2F4、NRF-1、CCAAT、YY1和ACTACAnnTCC在双向启动子中过度富集，而大多数（73%）已知的脊椎动物基序则低富集。我们在人类基因组的118个区域进行了染色质免疫沉淀（ChIP），随后对GABPA进行定量PCR，结果表明它与双向启动子的结合比单向启动子更频繁，并且其位置特异性评分矩阵对结合具有高度预测性。活跃转录的特征，如RNA聚合酶II以及修饰组蛋白H3K4me2、H3K4me3和H3ac的占据，在双向启动子周围的区域中过度富集，这表明在给定细胞中，反向基因转录的比例高于其他基因。因此，对全基因组微阵列数据的分析表明，68%的反向基因被转录，而所有人类基因的这一比例为44%。通过结合公开可用的ENCODE数据的分析和对GABPA的详细研究，我们从广度和深度上对双向启动子进行了调查，从而获得了有关其基序组成和双向调控模式的生物学见解。
