The Dynamic Regulation of G-Quadruplex DNA Structures by Cytosine Methylation

Abstract

It is well known that certain non B-DNA structures, including G-quadruplexes, are key elements that can regulate gene expression. Here, we explore the theory that DNA modifications, such as methylation of cytosine, could act as a dynamic switch by promoting or alleviating the structural formation of G-quadruplex structures in DNA or RNA. The interaction between epigenetic DNA modifications, G4 formation, and the 3D architecture of the genome is a complex and developing area of research. Although there is growing evidence for such interactions, a great deal still remains to be discovered. In vivo, the potential effect that cytosine methylation may have on the formation of DNA structures has remained largely unresearched, despite this being a potential mechanism through which epigenetic factors could regulate gene activity. Such interactions could represent novel mechanisms for important biological functions, including altering nucleosome positioning or regulation of gene expression. Furthermore, promotion of strand-specific G-quadruplex formation in differentially methylated genes could have a dynamic role in directing X-inactivation or the control of imprinting, and would be a worthwhile focus for future research.

Analysis of Nucleotide Variations in Human G-Quadruplex Forming Regions Associated with Disease States

“…G4s are formed due to the intricate balance between the folding energy by a nick in the DNA [122], methylated guanines [123], and guanines available for stacking [124]. The balance between the hypomethylated and hypermethylated G-rich regions near promoters (despite cytosine deamination and cytosine methylation) results in preserved CpG islands across mammalian genomes [125], which are maintained by G4 structures that act to sequester DNMT1, contributing to the CpG hypomethylation [107].…”

5-Hydroxymethylcytosine: the many faces of the sixth base of mammalian DNA

“…G4s are shown to form not only in telomeric regions but also throughout the genome in promoters, replication start sites, 138 therefore partly overlapping with methylation sites. 139 While some studies find no marked changes in the formation or stability of G4 structures after incorporation of hmC, 140 others report more complex results, 138 and infer their significance from the perspective of structural impact on promoter G4s formation in senescent cells.…”

Methylation across the central dogma in health and diseases: new therapeutic strategies

“…DNA methylation also modulates the formation of certain non-canonical DNA (non-B DNA) structures including G-quadruplexes, which affects gene expression. 153 Methylation in the mRNA coding sequence (CDS) including m 5 C and m 6 A can regulate codon-anticodon interactions, influencing translation efficiency in a codon-specific manner. 85 , 154 Moreover, the three-dimensional (3D) structures of mRNAs can be altered or stabilized upon methylation, which regulates their stability, localization, splicing, and translation efficiency.…”