Guanine quadruplex DNA structure restricts methylation of CpG dinucleotides genome-wide

Abstract

Cytosine methylation in mammals is important for epigenetic control of the transcriptome. Although altered methylation is frequently encountered in disease situations, particularly cancer, the relationship between genome-wide methylation and DNA structure is poorly understood. It is now evident that alternative DNA forms are functionally relevant in replication, recombination and transcription. Herein, we researched the role of alternative DNA structure in cytosine methylation using quadruplex DNA as a case study. Our findings from analysis of 2.1 million CpGs in humans, across 12 tissues from the Human Epigenome Project (HEP), revealed a striking correlation within each tissue: CpGs with low methylation were enriched (P = 5.24E(-20)) whereas CpGs with high methylation were relatively depleted (P = 9.28E(-15)), within quadruplex-forming regions. This was further substantiated on considering 1.07E(8) methylcytosines from genome-wide sequencing within embryonic stem cells and differentiated fibroblasts. To further test the predictions we experimentally determined methylation in >600,000 CpGs across 18 individuals using bisulfite mapping and found significantly low methylation of CpGs within quadruplex-forming regions (P = 1.36E(-08)). Together, these suggest the role of guanine-quadruplexes in CpG methylation and directly impact our understanding of the inter-relationship between DNA conformation and global cytosine methylation.

Identification of Genomic Features in Environmentally Induced Epigenetic Transgenerational Inherited Sperm Epimutations

“…Interestingly, previous reports show that G quadruplexes associate with zinc finger binding sites [48] and have a role in restricting DNA methylation [49] to influence chromatin dependent epigenetic instability [50]. Therefore, the distribution of G-quadruplexes across the different sets of DMR was analyzed.…”

“…Previous studies have shown that CpGs with high methylation are generally not present in G-quadruplexes (GGGG), which suggests that DNA methylation is restricted when G-quadruplex features exist [49]. G-quadruplex unwinding is a conserved mechanism which prevents G-quadruplex-induced damages such as genetic and epigenetic changes [56].…”

Mini- and Micro-Satellite Markers in Health, Disease and Evolution

“…In addition, changes in microsatellite length may infl uence the structural potential, which is important because G4 creation appears to limit the methylation at CpG dinucleotides [ 90 ]. Thus, the longer the microsatellites are, the higher the probability to have increased structural potential, and may in turn meddle in methylation [ 91 ].…”

Age-dependent methylation in epigenetic clock CpGs is associated with G-quadruplex, co-transcriptionally formed RNA structures and tentative splice sites

“…Furthermore, while DNA methylation regulates splicing of about 22% of alternative exons [7], the mechanism by which this occurs remains obscure [7–12]. Finally, there is evidence, albeit very limited, that DNA methylation is associated to DNA conformational characteristics [13,14]. …”