Genome-wide analysis reveals regulatory role of G4 DNA in gene transcription

Abstract

G-quadruplex or G4 DNA, a four-stranded DNA structure formed in G-rich sequences, has been hypothesized to be a structural motif involved in gene regulation. In this study, we examined the regulatory role of potential G4 DNA motifs (PG4Ms) located in the putative transcriptional regulatory region (TRR, -500 to +500) of genes across the human genome. We found that PG4Ms in the 500-bp region downstream of the annotated transcription start site (TSS; PG4M D500 ) are associated with gene expression. Generally, PG4M D500 -positive genes are expressed at higher levels than PG4M D500 -negative genes, and an increased number of PG4M D500 provides a cumulative effect. This observation was validated by controlling for attributes, including gene family, function, and promoter similarity. We also observed an asymmetric pattern of PG4M D500 distribution between strands, whereby the frequency of PG4M D500 in the coding strand is generally higher than that in the template strand. Further analysis showed that the presence of PG4M D500 and its strand asymmetry are associated with significant enrichment of RNAP II at the putative TRR. On the basis of these results, we propose a model of G4 DNA-mediated stimulation of transcription with the hypothesis that PG4M D500 contributes to gene transcription by maintaining the DNA in an open conformation, while the asymmetric distribution of PG4M D500 considerably reduces the probability of blocking the progression of the RNA polymerase complex on the template strand. Our findings provide a comprehensive view of the regulatory function of G4 DNA in gene transcription.

Transcriptional control by G-quadruplexes: In vivo roles and perspectives for specific intervention

“…Several reports suggest that G-quadruplexes act as transcriptional repressors by impeding transcription factor binding to duplex-DNA or stalling the progression of RNA polymerase, mostly when they are located downstream the transcription start site in the template strand. 2,[20][21][22] Conversely, other reports showed that G-quadruplex may enhance the transcription of particular genes by favoring the binding of specific transcription factors 2,12,22 or by holding the DNA molecule open thus facilitating the re-initiation of transcription 2,7,14,22 (Fig. 1B).…”

“…The current hypothesis states that transcription bubble generates regions of positive and negative supercoiling, which can be propagated along the DNA-helix until reaching sites susceptible of structural transitions. In this condition, transiently exposed singlestrand segments become able to fold as G-quadruplexes 7 (Fig. 1B).…”

G-quadruplex forming structural motifs in the genome of Deinococcus radiodurans and their regulatory roles in promoter functions

“…For example, G4 DNA located in the Electronic supplementary material The online version of this article (doi:10.1007/s00253-015-6808-6) contains supplementary material, which is available to authorized users. proximity of a promoter can downregulate gene expression while its presence at the far distance in the same strand or anywhere in the opposite strands could upregulate gene expression (Kennedy et al 1992;Cogoi et al 2006;Du et al 2008). It is known that monovalent cations such as Na + and K + can stabilize G4 structures by interacting in the central channels between each pair of tetrads (Burge et al 2006).…”

Transcription induces strand-specific mutations at the 5′ end of human genes

“…It is not known when and where such structures are formed, but several DNA sequence motifs have been suggested to have higher probability to form G-quadruplexes (Yadav et al 2008). Recent studies reveal an enrichment of such motifs in promoter regions and in the first 500 bp of human genes (Du et al 2008). Therefore, these G4 conformations have the potential to create a gradient of ssDNA of the nontemplate strand along human transcripts.…”

“…Beside R-loops, the non-B DNA conformations, Gquadruplexes (G4), also might be formed near the TSS of human genes on the nontranscribed strand (Du et al 2008). A formation of G4 structure in the nontemplate strand and, in parallel, a formation of R-loop on the template strand, is often called Gloops and has been also observed in different situations (Duquette et al 2004).…”