Abstract
Recently, we reported the co-transcriptional formation of DNA:RNA hybrid G-quadruplex (HQ) structure by the non-template DNA strand and nascent RNA transcript, which in turn modulates transcription under both in vitro and in vivo conditions. Here we present bioinformatic analysis on putative HQ-forming sequences (PHQS) in the genomes of eukaryotic organisms. Starting from amphibian, PHQS motifs are concentrated in the immediate 1000-nt region downstream of transcription start sites, implying their potential role in transcription regulation. Moreover, their occurrence shows a strong bias toward the non-template versus the template strand. PHQS has become constitutional in genes in warm-blooded animals, and the magnitude of the strand bias correlates with the ability of PHQS to form HQ, suggesting a selection based on HQ formation. This strand bias is reversed in lower species, implying that the selection of PHQS/HQ depended on the living temperature of the organisms. In comparison with the putative intramolecular G-quadruplex-forming sequences (PQS), PHQS motifs are far more prevalent and abundant in the transcribed regions, making them the dominant candidates in the formation of G-quadruplexes in transcription. Collectively, these results suggest that the HQ structures are evolutionally selected to function in transcription and other transcription-mediated processes that involve guanine-rich non-template strand.
Highlights
G-quadruplex, a four-stranded secondary structure formed by guanine-rich (G-rich) nucleic acids, is gaining increasing attention owing to its potential role in physiological and pathological processes [1,2,3,4]
Because the formation of hybrid G-quadruplex (HQ) in transcription requires a minimum of two G-tracts from the DNA strand, our searching pattern was adopted from the one G!3 -(N1-7-G!3)!3 that has been used in searches for Putative G-quadruplex sequences (PQS) in genomes in the original [6,7] and many later works [13,22,23,24,25,26,27,28,29,30,31,34,35,36,37] by reducing the minimal number of G-tracts from four to two
Similar results were obtained for the EGR1, MAZ and SP1 motifs with respect to their influence on the occurrence of putative HQforming sequences (PHQS) and contribution to the strand bias, in a reduced magnitude. These results indicated that CpG islands, transcription factor binding sites (TFBSs) and similar G-rich regulatory motifs provide a source for the enrichment of PHQS and they were differentially selected on the two DNA strands to promote HQ formation
Summary
G-quadruplex, a four-stranded secondary structure formed by guanine-rich (G-rich) nucleic acids, is gaining increasing attention owing to its potential role in physiological and pathological processes [1,2,3,4]. Because of its abundance in promoter regions [13], a more general function of Gquadruplex in a genome is believed to play a role in transcription regulation. This functionality is first demonstrated for the intramolecular G-quadruplex structure upstream of the P1 promoter of C-MYC that controls the transcriptional activation of the gene [14] and later for the G-quadruplex structures in many other genes [15,16,17,18,19,20,21]. Bioinformatic searches of genomic DNA revealed that PQS are enriched around transcription start sites (TSS) in a variety of organisms, providing a strong support to a general role of G-quadruplex structures in transcription [6,7,22,23,24,25,26,27,28,29,30,31]
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