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Comprehensive annotation of bidirectional promoters identifies co-regulation among breast and ovarian cancer genes.

ABSTRACT: 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.

SUBMITTER: Yang MQ

PROVIDER: S-EPMC1853124 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: A "bidirectional gene pair" is defined as two adjacent genes which are located on opposite strands of DNA with transcription start sites (TSSs) not more than 1000 base pairs apart and the intergenic region between two TSSs is commonly designated as a putative "bidirectional promoter". Individual examples of bidirectional gene pairs have been reported for years, as well as a few genome-wide analyses have been studied in mammalian and human genomes. However, no genome-wide analysis of bidirectional genes for plants has been done. Furthermore, the exact mechanism of this gene organization is still less understood. RESULTS: We conducted comprehensive analysis of bidirectional gene pairs through the whole Arabidopsis thaliana genome and identified 2471 bidirectional gene pairs. The analysis shows that bidirectional genes are often coexpressed and tend to be involved in the same biological function. Furthermore, bidirectional gene pairs associated with similar functions seem to have stronger expression correlation. We pay more attention to the regulatory analysis on the intergenic regions between bidirectional genes. Using a hierarchical stochastic language model (HSL) (which is developed by ourselves), we can identify intergenic regions enriched of regulatory elements which are essential for the initiation of transcription. Finally, we picked 27 functionally associated bidirectional gene pairs with their intergenic regions enriched of regulatory elements and hypothesized them to be regulated by bidirectional promoters, some of which have the same orthologs in ancient organisms. More than half of these bidirectional gene pairs are further supported by sharing similar functional categories as these of handful experimental verified bidirectional genes. CONCLUSION: Bidirectional gene pairs are concluded also prevalent in plant genome. Promoter analyses of the intergenic regions between bidirectional genes could be a new way to study the bidirectional gene structure, which may provide a important clue for further analysis. Such a method could be applied to other genomes.

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Comprehensive annotation of bidirectional promoters identifies co-regulation among breast and ovarian cancer genes.

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