DNA Methylation: Genomewide Distribution, Regulatory Mechanism and Therapy Target

Abstract

DNA methylation is the most important epigenetic modification involved in the regulation of transcription, imprinting, establishment of X-inactivation, and the formation of a chromatin structure. DNA methylation in the genome is often associated with transcriptional repression and the formation of closed heterochromatin. However, the results of genome-wide studies of the DNA methylation pattern and transcriptional activity of genes have nudged us toward reconsidering this paradigm, since the promoters of many genes remain active despite their methylation. The differences in the DNA methylation distribution in normal and pathological conditions allow us to consider methylation as a diagnostic marker or a therapy target. In this regard, the need to investigate the factors affecting DNA methylation and those involved in its interpretation becomes pressing. Recently, a large number of protein factors have been uncovered, whose ability to bind to DNA depends on their methylation. Many of these proteins act not only as transcriptional activators or repressors, but also affect the level of DNA methylation. These factors are considered potential therapeutic targets for the treatment of diseases resulting from either a change in DNA methylation or a change in the interpretation of its methylation level. In addition to protein factors, a secondary DNA structure can also affect its methylation and can be considered as a therapy target. In this review, the latest research into the DNA methylation landscape in the genome has been summarized to discuss why some DNA regions avoid methylation and what factors can affect its level or interpretation and, therefore, can be considered a therapy target.

Keywords: DNA methylation; DNA methyltransferases; G-quadruplexes; TET dioxydenases; methyl-DNA binding proteins.

Fig. 1

Cytosine methylation and demethylation scheme

Fig. 2

Landscape of the DNA repetitive sequences. (A) Location of various repeating sequences on a chromosome. (B) DNA methylation profile in the genome, depending on the activity of promoters and enhancers and the presence of CpG islands

Fig. 3

Binding scheme (A) DNMT3a/3b to unmodified H3K4, the presence of H3K4me3 prevents the ADD domain from binding to DNA, which leads to autoinhibition of the enzyme; (B) DNMT1 to DNA, the interaction with unmethylated DNA leads to inhibition of the catalytic domain [29, 30]

Fig. 4

Distribution of potential G4 sequences in CpG islands. (A) The proportion of CpG islands with G4, (B) the distribution density of G4 near CpG islands depending on the localization in the genome. (C) G4 density and (D) GC composition in promoter regions depending on the presence of CpG islands

Fig. 5

Model of the functional significance of the interaction between the MBD2 protein and the NuRD repression complex in the regulation of the gamma globin gene in beta-telassemia [122, 123]