Transcription factor binding and modified histones in human bidirectional promoters

Abstract

Bidirectional promoters have received considerable attention because of their ability to regulate two downstream genes (divergent genes). They are also highly abundant, directing the transcription of ∼11% of genes in the human genome. We categorized the presence of DNA sequence motifs, binding of transcription factors, and modified histones as overrepresented, shared, or underrepresented in bidirectional promoters with respect to unidirectional promoters. We found that a small set of motifs, including GABPA, MYC, E2F1, E2F4, NRF-1, CCAAT, YY1, and ACTACAnnTCC are overrepresented in bidirectional promoters, while the majority (73%) of known vertebrate motifs are underrepresented. We performed chromatin-immunoprecipitation (ChIP), followed by quantitative PCR for GABPA, on 118 regions in the human genome and showed that it binds to bidirectional promoters more frequently than unidirectional promoters, and its position-specific scoring matrix is highly predictive of binding. Signatures of active transcription, such as occupancy of RNA polymerase II and the modified histones H3K4me2, H3K4me3, and H3ac, are overrepresented in regions around bidirectional promoters, suggesting that a higher fraction of divergent genes are transcribed in a given cell than the fraction of other genes. Accordingly, analysis of whole-genome microarray data indicates that 68% of divergent genes are transcribed compared with 44% of all human genes. By combining the analysis of publicly available ENCODE data and a detailed study of GABPA, we survey bidirectional promoters with breadth and depth, leading to biological insights concerning their motif composition and bidirectional regulatory mode.

Genome wide study of NF-Y type CCAAT boxes in unidirectional and bidirectional promoters in human and mouse

“…In bidirectional promoters, the boxes were found above chance. This finding is in agreement with a study using chromatin-immunoprecipitation (ChIP) on 118 regions in the human genome that showed that CCAAT boxes, among a few other small motifs, are over-represented in bidirectional promoters, in comparison to unidirectional ones (Lin et al, 2007). Interestingly, our analysis of a much larger set of promoters further shows that in unidirectional promoters, the boxes are also found above chance, provided that they have a low number of mismatches from consensus.…”

“…Previous studies suggest that NF-Y type CCAAT boxes are common regulators of bidirectional mammalian promoters (Lin et al, 2007;Zanotto et al, 2009). However, several questions remain regarding their role as regulators of gene expression.…”

Characterization of the human CREB3L2 gene promoter

“…The impact, if any, of expression of AKR1D1 on CREB3L2 is unknown. In general, bidirectional promoters lack TATA boxes, are both GC-rich and enriched in CpG islands, and have an overrepresented set of motifs, including GABPA, MYC, E2F1, E2F4, NRF-1, CCAAT, YY1, and ACTACAnnTCC (12). GABPA, E2F1 and CCAAT motifs are present in the region between +1 of CREB3L2 and +1 of the AK058142 trancsript.…”

Gene clustering pattern, promoter architecture, and gene expression stability in eukaryotic genomes

“…The most likely proposed function of such clustering is to coregulate two adjacent genes by a single bidirectional promoter. However, coexpression of two adjacent head-to-head genes does not occur much more often than would be expected by chance (7,8). Thus, head-to-head clustering might have other regulatory roles.…”