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

2Department of BiologicalSciences, Kent State University, Kent, Ohio 44242, USA.
BMC Genomics (Impact Factor: 3.99). 05/2009; 10(1):189. DOI: 10.1186/1471-2164-10-189
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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.
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.
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.

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    • "e l s e v i e r . c o m / l o c a t e / y p l a s in many other genomes, including yeast, plants, invertebrates and vertebrates (Adachi and Lieber, 2002; Herr and Harris, 2004; Takai and Jones, 2004; Trinklein et al., 2004; Koyanagi et al., 2005; Engström et al., 2006; Li et al., 2006; Yang and Elnitski, 2008a,b; Yang et al., 2008; Piontkivska et al., 2009; Wang et al., 2009; Woo and Li, 2011), suggesting an important biological significance for this regulatory configuration. It has been shown that some bidirectional promoters, such as those of the histone genes, regulate the transcription of pair of genes that need coordinated expression to maintain stoichiometric relationships (e.g. "
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    ABSTRACT: Regulation of gene expression plays important role in cellular functions. With the development of sequencing techniques, more and more genomes are available and genome-wide analyses of genomic structures that may affect gene expression regulation are now possible. Analyses of several genomes have found a class of regulatory regions that contain elements that initiate transcription of two different genes positioned with a head-to-head arrangement in two opposite directions. These regulatory regions are known as bidirectional promoters. Although bidirectional promoters have been known for years, recent genome-scale studies have shown that the regulation of the expression of up to 10% of the genes are controlled by bidirectional promoters. These findings are based mostly on computational work and only a limited number of putative bidirectional promoters have been experimentally validated. Developing methods to study bidirectional promoters will allow researchers to understand how these regions are regulated and the roles that divergent transcription plays in the expression of genes. Here, we have developed a novel dual-fluorescence reporter gene vector to study the transcriptional output of bidirectional promoters. We demonstrate that this vector is capable of expressing reporter genes under the control of bidirectional promoters, using the known human OSGEP/APEX bidirectional promoter.
    Plasmid 05/2014; 74. DOI:10.1016/j.plasmid.2014.05.001 · 1.58 Impact Factor
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    • "In addition to the mechanism of gene duplication, recent evidence accumulates to support the diversification of the gene repertoire through the emergence of novel genes from previously untranscribed regions. Examples of newly emerged lineage-specific genes include our previous work in cow [10], and extend to organisms as diverse as Plasmodium vivax [11], yeast [12], [13], Drosophila [14], [15], [16], and primates [17], [18], [19]. Nonetheless, Kaessmann recently highlighted the lack of a specific mechanism to account for the emergence of new genes from genomic regions lacking prior gene functions, i.e. “from scratch” [20]. "
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    ABSTRACT: The diversification of gene functions has been largely attributed to the process of gene duplication. Novel examples of genes originating from previously untranscribed regions have been recently described without regard to a unifying functional mechanism for their emergence. Here we propose a model mechanism that could generate a large number of lineage-specific novel transcripts in vertebrates through the activation of bidirectional transcription from unidirectional promoters. We examined this model using human transcriptomic and genomic data and identified evidence consistent with the emergence of more than 1,000 primate-specific transcripts. These are transcripts with low coding potential and virtually no functional annotation. They initiate at less than 1 kb upstream of an oppositely transcribed conserved protein coding gene, in agreement with the generally accepted definition of bidirectional promoters. We found that the genomic regions upstream of ancestral promoters, where the novel transcripts in our dataset reside, are characterized by preferential accumulation of transposable elements. This enhances the sequence diversity of regions located upstream of ancestral promoters, further highlighting their evolutionary importance for the emergence of transcriptional novelties. By applying a newly developed test for positive selection to transposable element-derived fragments in our set of novel transcripts, we found evidence of adaptive evolution in the human lineage in nearly 3% of the novel transcripts in our dataset. These findings indicate that at least some novel transcripts could become functionally relevant, and thus highlight the evolutionary importance of promoters, through their capacity for bidirectional transcription, for the emergence of novel genes.
    PLoS ONE 02/2013; 8(2):e57323. DOI:10.1371/journal.pone.0057323 · 3.23 Impact Factor
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    • "Compared to adjacently located gene pairs arranged in convergent and tandem configuration, there are more divergent gene pairs with a distance between transcription start sites of < 1000 bp. The percentage of bidirectional gene pairs is significantly larger than expected by chance [2,4]. "
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    ABSTRACT: Background Bidirectional promoters are shared promoter sequences between divergent gene pair (genes proximal to each other on opposite strands), and can regulate the genes in both directions. In the human genome, > 10% of protein-coding genes are arranged head-to-head on opposite strands, with transcription start sites that are separated by < 1,000 base pairs. Many transcription factor binding sites occur in the bidirectional promoters that influence the expression of 2 opposite genes. Recently, RNA polymerase II (RPol II) ChIP-seq data are used to identify the promoters of coding genes and non-coding RNAs. However, a bidirectional promoter with RPol II ChIP-Seq data has not been found. Results In some bidirectional promoter regions, the RPol II forms a bi-peak shape, which indicates that 2 promoters are located in the bidirectional region. We have developed a computational approach to identify the regulatory regions of all divergent gene pairs using genome-wide RPol II binding patterns derived from ChIP-seq data, based upon the assumption that the distribution of RPol II binding patterns around the bidirectional promoters are accumulated by RPol II binding of 2 promoters. In HeLa S3 cells, 249 promoter pairs and 1094 single promoters were identified, of which 76 promoters cover only positive genes, 86 promoters cover only negative genes, and 932 promoters cover 2 genes. Gene expression levels and STAT1 binding sites for different promoter categories were therefore examined. Conclusions The regulatory region of bidirectional promoter identification based upon RPol II binding patterns provides important temporal and spatial measurements regarding the initiation of transcription. From gene expression and transcription factor binding site analysis, the promoters in bidirectional regions may regulate the closest gene, and STAT1 is involved in primary promoter.
    BMC Medical Genomics 01/2013; 6(1). DOI:10.1186/1755-8794-6-S1-S5 · 2.87 Impact Factor
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