Abstract
G-quadruplexes (G4s) are among the best-characterized DNA secondary structures and are enriched in regulatory regions, especially promoters, of several prokaryote and eukaryote genomes, indicating a possible role in cis regulation of genes. Many studies have focused on evaluating the impact of specific G4-forming sequences in the promoter regions of genes. However, the lack of correlation between the presence of G4s and the functional impact on cis gene regulation, evidenced by the variable expression fold change in the presence of G4 stabilizers, shows that not all G4s affect transcription in the same manner. This indicates that the regulatory effect of the G4 is significantly influenced by its position, the surrounding DNA topology, and other environmental factors within the cell. In this review, we compare individual gene studies with high-throughput differential expression studies to highlight the importance of formulating a combined approach that can be applied in humans, bacteria, and viruses to better understand the effect of G4-mediated gene regulation.
Highlights
The landscape of genomic DNA has shown a myriad of alternate DNA structures such as cruciform (Brazda et al, 2011), G-quadruplexes (G4s) (Kwok and Merrick, 2017), triplexes (Frank-Kamenetskii and Mirkin, 1995), and i-motifs (Abou Assi et al, 2018)
G4-mediated cis-regulatory activity has been confirmed by reporter assays in various genes such as CMYC, C-KIT, and BCL2 (Siddiqui-Jain et al, 2002; Ashman and Griffith, 2013; Le et al, 2013)
These ligands display considerable selectivity for G4 structures over single-stranded and double-stranded DNA, it is essential to study the effect of ligand binding to untargeted G4-forming regions in the genome (Figure 1)
Summary
Specialty section: This article was submitted to Evolutionary and Genomic Microbiology, a section of the journal Frontiers in Genetics. G-quadruplexes (G4s) are among the best-characterized DNA secondary structures and are enriched in regulatory regions, especially promoters, of several prokaryote and eukaryote genomes, indicating a possible role in cis regulation of genes. The lack of correlation between the presence of G4s and the functional impact on cis gene regulation, evidenced by the variable expression fold change in the presence of G4 stabilizers, shows that not all G4s affect transcription in the same manner. This indicates that the regulatory effect of the G4 is significantly influenced by its position, the surrounding DNA topology, and other environmental factors within the cell.
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