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Title: Comprehensive Annotation of Bidirectional Promoters Identifies Co-Regulation among Breast and Ovarian Cancer Genes}
Article:
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.
Introduction:
Bidirectional gene pairs are defined as two genes arranged head-to-head( adjacent 5′ ends) on opposite strands of DNA and within 1, 000 bp of one another[1]. The definition of 1, 000 bp is supported by analyses of Trinklein et al.[2], which show an enrichment of genes whose 5′ ends are on opposite strands and within 1, 000 bp and no enrichment of genes with 5′ ends on the same strand at this distance. The sequences between the transcription start sites of bidirectional gene pairs are known as bidirectional promoters, and they influence expression of both adjacent genes. Bidirectional promoters represent a regulatory construction that is utilized repeatedly in the human genome, with 1, 352 known examples[2]. Despite substantial interest in these promoters[1–3], the biological significance of this regulatory architecture is not well-established. The bidirectional arrangement is conserved among species, suggesting that it is functionally important[2]. Furthermore, a strand-specific pattern of the nucleotides in these promoters[3] could play a role in binding regulatory proteins. For instance, SP1-binding sites have been suggested as key regulators of CpG island promoters[4]. If groups of bidirectional promoters are similarly regulated, then distantly located genes under the control of these promoters should show common expression patterns. Additional regulatory factors must also be involved, because genes that form a bidirectional pair are not always expressed together. Experimental studies show that within a pair, genes can be expressed in a mutually exclusive manner[2]. How the intervening promoter sequence preferentially activates one gene versus another is currently unknown. The categories of genes regulated by these promoters imply that specialized transcription factor binding sites could regulate expression of these genes. For instance, bidirectional promoters regulate DNA repair genes[1]. DNA repair genes frequently play a role in cancer that is elicited through mutations in their coding sequences. However, another plausible scenario toward the development of cancer comes from the misregulation of bidirectional promoters, especially if they contain common transcription factor binding sites. These sites would be candidates to explain a general mechanism in which regulatory disruptions at bidirectional promoters could play a pivotal role in cancer. We developed a new algorithm to comprehensively map bidirectional promoters in the human genome using spliced expressed sequence tags( ESTs). The extended set of bidirectional promoters elucidates relationships among genes regulated by bidirectional promoters through co-expression networks. We show evidence that a subset of these promoters, which regulate genes implicated in breast and ovarian cancers, contain transcription factor binding sites in common.
Discussion:
In addition to common expression patterns, bidirectional promoters have the propensity for mis-regulation. Five of the nine breast and ovarian cancer genes have evidence of aberrant methylation affecting their expression levels in somatic tumors( see Table 1). Moreover, methylation of the MLH1 bidirectional promoter[23] is almost exclusively responsible for cases of sporadic mismatch-repair deficiency in colon cancer[24]. This gene is located at the center of our shared expression network. The development of sporadic cancer is consistent with the loss of important functions of genes regulated by bidirectional promoters( e. g., genome stability, transcription, cell cycle control, nucleotide binding, tumor suppression, or mitochondrial stress response). These functions extend beyond the role of DNA repair, and are consistent with a much broader category of functions involved in the response to DNA damage. Loss of any of these cellular activities could lead to a neoplastic phenotype. Additionally, these functions argue that mis-regulation of bidirectional promoters could extend beyond breast and ovarian malignancies. Epigenetic modifications associated with sporadic breast and ovarian cancers—such as silencing of bidirectional promoters—suggest a parallel mechanism by which regulatory disturbances could affect similar sets of genes as do mutations. Methylation could impede the binding of a protein( such as an ETS factor family member), putatively affecting the expression of two genes regulated by the bidirectional promoter. It has been previously shown that methylation of a bidirectional promoter inhibits expression of both associated genes[25]. We propose that bidirectional promoters be explored comprehensively as targets of aberrant methylation. We have identified a number of genes implicated in sporadic breast and ovarian cancers that are regulated in this manner.
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 .