Abstract
Approximately 10% of genes in the human genome are distributed such that their transcription start sites are located less than 1 kb apart on opposite strands. These divergent gene pairs have a single intergenic segment of DNA, which in some cases appears to share regulatory elements, but it is unclear whether these regions represent functional bidirectional promoters or two overlapping promoters. A recent study showed that divergent promoters are enriched for consensus binding sequences of a small group of transcription factors, including the ubiquitous ets-family transcription factor GA-binding protein (GABP). Here we show that GABP binds to more than 80% of divergent promoters in at least one cell type. Furthermore, we demonstrate that GABP binding is correlated and associated with bidirectional transcriptional activity in a luciferase transfection assay. In addition, we find that the addition of a strict consensus GABP site into a set of promoters that normally function in only one direction significantly increases activity in the opposite direction in 67% of cases. Our findings demonstrate that GABP regulates the majority of divergent promoters and suggest that bidirectional transcriptional activity is mediated through GABP binding and transactivation at both divergent and nondivergent promoters.
Highlights
Since the discovery that more than 10% of the proteincoding genes in the human genome are located on opposite strands with transcription start sites less than 1 kb away from each other, there has been considerable interest in determining why such an arrangement exists [1,2,3]
Surveys of the locations of genes in the human genome have revealed that a surprising number of genes, greater than 10%, have transcription start sites within 1 kb of one another on opposite strands
We find that it regulates a large number of human genes, including the majority of divergent genes, and that its binding is associated with, correlated with, and sufficient for bidirectional transcriptional activity
Summary
Since the discovery that more than 10% of the proteincoding genes in the human genome are located on opposite strands with transcription start sites less than 1 kb away from each other, there has been considerable interest in determining why such an arrangement exists [1,2,3]. Divergent promoters exhibit increased colocation with CpG islands, a paucity of TATA elements, and an enriched subset of transcription factor binding sites [3,9] These features suggest that the functional behavior of divergent promoters is distinct from that of general promoters. Another study using integrating lentiviral vectors designed for gene therapy demonstrated that several general promoters were capable of transcribing marker genes in both directions, suggesting that general promoters can be capable of bidirectional transcription in a genomic context [11] This raises the question of whether bidirectional activity is the default state for certain promoters in the absence of directional ‘‘repressors.’’ Despite some distinctive sequence characteristics, no clear functional features differentiate divergent from general promoters
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