Diversity of core promoter elements comprising human bidirectional promoters

<p>Abstract</p> <p>Background</p> <p>Bidirectional promoters lie between adjacent genes, which are transcribed from opposite strands of DNA. The functional mechanisms underlying the activation of bidirectional promoters are currently uncharacterised. To define the core promoter elements of bidirectional promoters in human, we mapped motifs for TATA, INR, BRE, DPE, INR, as well as CpG-islands.</p> <p>Results</p> <p>We found a consistently high correspondence between C+G content, CpG-island presence and an average expression level increasing the median level for all genes in bidirectional promoters. These CpG-rich promoters showed discrete initiation patterns rather than broad regions of transcription initiation, as are typically seen for CpG-island promoters. CpG-islands encompass both TSSs within bidirectional promoters, providing an explanation for the symmetrical co-expression patterns of many of these genes. In contrast, TATA motifs appear to be asymmetrically positioned at one TSS or the other.</p> <p>Conclusion</p> <p>Our findings demonstrate that bidirectional promoters utilize a variety of core promoter elements to initiate transcription. CpG-islands dominate the regulatory landscape of this group of promoters.</p

Prediction-based approaches to characterize bidirectional promoters in the mammalian genome

<p>Abstract</p> <p>Background</p> <p>Machine learning approaches are emerging as a way to discriminate various classes of functional elements. Previous attempts to create Regulatory Potential (RP) scores to discriminate functional DNA from nonfunctional DNA included using Markov models trained to identify sequences from promoters and enhancers from ancestral repeats. We proposed that knowledge gleaned from those methods could be further refined using a multiple class predictor to separate classes of promoter elements from enhancers or nonfunctional DNA.</p> <p>Results</p> <p>We extended our previous work, which identified over 5,000 candidate bidirectional promoters in the human genome, to map the orthologous promoter regions in the mouse genome. Our algorithm measured the robustness of evidence provided by the spliced EST annotations and incorporated evidence from annotations of UCSC Known Genes and GenBank mRNA. In preparation for de novo prediction of this promoter type, we examined characteristic features of the dataset as a whole. For instance, bidirectional promoters score very highly among all functional elements for Regulatory Potential Scores. This result was unexpected due to the limited sequence conservation found in these noncoding regions. We demonstrate that bidirectional promoters can be classified apart from other genomic features including non-bidirectional promoters, i.e. those promoters having no nearby upstream genes. Furthermore bidirectional promoters consistently score at the level of very highly conserved functional elements in the genome- developmental enhancers. The high scores are due to sequence-based characteristics within the promoters, not the surrounding exons. These results indicate that high-scoring RP regions can be deconvoluted into various functional classes of genomic elements. Using a multiple class predictor we are able to discriminate bidirectional promoters from enhancers, non-bidirectional promoters, and non-promoter regions on the basis of RP scores and CpG islands.</p> <p>Conclusions</p> <p>We examine orthology at bidirectional promoters, use discriminatory machine learning approaches to differentiate multiple types of promoters from other functional and nonfunctional features in the genome and begin the process of deconvoluting classes of functional regions that score well with RP scores. These types of approaches precede supervised learning techniques to discover unannotated promoter regions.</p

Comparative analyses of bidirectional promoters in vertebrates

<p>Abstract</p> <p>Background</p> <p>Orthologous genes with deep phylogenetic histories are likely to retain similar regulatory features. In this report we utilize orthology assignments for pairs of genes co-regulated by bidirectional promoters to map the ancestral history of the promoter regions.</p> <p>Results</p> <p>Our mapping of bidirectional promoters from humans to fish shows that many such promoters emerged after the divergence of chickens and fish. Furthermore, annotations of promoters in deep phylogenies enable detection of missing data or assembly problems present in higher vertebrates. The functional importance of bidirectional promoters is indicated by selective pressure to maintain the arrangement of genes regulated by the promoter over long evolutionary time spans. Characteristics unique to bidirectional promoters are further elucidated using a technique for unsupervised classification, known as ESPERR.</p> <p>Conclusion</p> <p>Results of these analyses will aid in our understanding of the evolution of bidirectional promoters, including whether the regulation of two genes evolved as a consequence of their proximity or if function dictated their co-regulation.</p

Genomic features defining exonic variants that modulate splicing

A comparative analysis of SNPs and their exonic and intronic environments identifies the features predictive of splice affecting variants

Comprehensive Annotation of Bidirectional Promoters Identifies Co-Regulation among Breast and Ovarian Cancer Genes

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

Cross-species mapping of bidirectional promoters enables prediction of unannotated 5' UTRs and identification of species-specific transcripts

BACKGROUND: Bidirectional promoters are shared regulatory regions that influence the expression of two oppositely oriented genes. This type of regulatory architecture is found more frequently than expected by chance in the human genome, yet many specifics underlying the regulatory design are unknown. Given that the function of most orthologous genes is similar across species, we hypothesized that the architecture and regulation of bidirectional promoters might also be similar across species, representing a core regulatory structure and enabling annotation of these regions in additional mammalian genomes. RESULTS: By mapping the intergenic distances of genes in human, chimpanzee, bovine, murine, and rat, we show an enrichment for pairs of genes equal to or less than 1,000 bp between their adjacent 5' ends ("head-to-head") compared to pairs of genes that fall in the same orientation ("head-to-tail") or whose 3' ends are side-by-side ("tail-to-tail"). A representative set of 1,369 human bidirectional promoters was mapped to orthologous sequences in other mammals. We confirmed predictions for 5' UTRs in nine of ten manual picks in bovine based on comparison to the orthologous human promoter set and in six of seven predictions in human based on comparison to the bovine dataset. The two predictions that did not have orthology as bidirectional promoters in the other species resulted from unique events that initiated transcription in the opposite direction in only those species. We found evidence supporting the independent emergence of bidirectional promoters from the family of five RecQ helicase genes, which gained their bidirectional promoters and partner genes independently rather than through a duplication process. Furthermore, by expanding our comparisons from pairwise to multispecies analyses we developed a map representing a core set of bidirectional promoters in mammals. CONCLUSION: We show that the orthologous positions of bidirectional promoters provide a reliable guide to directly annotate over one thousand regulatory regions in sequences of mammalian genomes, while also serving as a useful tool to predict 5' UTR positions and identify genes that are novel to a single species

Improvements to GALA and dbERGE II: databases featuring genomic sequence alignment, annotation and experimental results

We describe improvements to two databases that give access to information on genomic sequence similarities, functional elements in DNA and experimental results that demonstrate those functions. GALA, the database of Genome ALignments and Annotations, is now a set of interlinked relational databases for five vertebrate species, human, chimpanzee, mouse, rat and chicken. For each species, GALA records pairwise and multiple sequence alignments, scores derived from those alignments that reflect the likelihood of being under purifying selection or being a regulatory element, and extensive annotations such as genes, gene expression patterns and transcription factor binding sites. The user interface supports simple and complex queries, including operations such as subtraction and intersections as well as clustering and finding elements in proximity to features. dbERGE II, the database of Experimental Results on Gene Expression, contains experimental data from a variety of functional assays. Both databases are now run on the DB2 database management system. Improved hardware and tuning has reduced response times and increased querying capacity, while simplified query interfaces will help direct new users through the querying process. Links are available at http://www.bx.psu.edu/