Enzymatic DNA Methylation Is an Epigenetic Control for Genetic Functions of the Cell

Abstract

In eukaryotic cells nuclear DNA is subjected to enzymatic methylation resulting in formation of 5-methylcytosine residues mainly in CG and CNG sequences. In plants and animals, this DNA methylation is species-, tissue-, and organelle-specific. It changes (diminishes) with age and is regulated by hormones. On the other hand, genome methylation can control hormonal signal. There are replicative and post-replicative DNA methylations. They are served by multiple DNA-methyltransferases with different site specificity. Replication is accompanied by appearance of hemi-methylated sites in DNA; pronounced asymmetry of DNA chain methylation disappears at the end of the cell cycle; a model of regulation of replication by DNA methylation is suggested. DNA methylation controls all genetic processes in the cell (replication, transcription, DNA repair, recombination, gene transposition) and it is a mechanism of cell differentiation, gene discrimination, and silencing. Prohibition of DNA methylation stops development (embryogenesis), switches on apoptosis, and is usually lethal. Distortions in DNA methylations result in cancerous cell transformation, and the DNA methylation pattern is one of the safe cancer diagnostics at early stages of carcinogenesis. The malignant cell has a different DNA methylation pattern and a set of DNA-methyltransferase activities expressed as compared with normal cells. Inhibition of DNA methylation in plants is accompanied by induction of genes of seed storage proteins and flowering. In eukaryotes one and the same gene can be methylated both on cytosine and adenine residues; thus, there are, at least, two different and probably interdependent systems of DNA methylation in the cell. First higher eukaryotic adenine DNA-methyltransferase was isolated from plants; this enzyme methylates DNA with formation of N6-methyladenine residues in the sequence TGATCA --> TGm6ATCA. Plants have AdoMet-dependent endonucleases sensitive to DNA methylation status; therefore, like microorganisms, plants seem to have a restriction-modification (R-S) system. Revelation of an essential role of DNA methylation in the regulation of genetic processes has laid a foundation for and materialized epigenetics and epigenomics.

Regulation of mammalian gene expression by retroelements and non‐coding tandem repeats

“…After their initial insertion, retrotransposons (RTs) undergo transcriptional silencing, which involves CpG methylation in DNA (58) and may also involve repressive modifications of histones. The ''genome defense'' hypothesis suggests that CpG methylation initially arose in evolution for silencing and neutralizing the gene activities of transposable elements and was subsequently recruited for repression of genes (59) but there are other hypotheses on the evolutionary origin of DNA methylation.…”

Age-Dependent Change in the Morphology of Nucleoli and Methylation of Genes of the Nucleolar Organizer Region in Japanese Quail (<I>Coturnix japonica</I>) Model (Temminck and Schlegel, 1849) (Galliformes: Aves)

“…It is also characterized by specificity within particular tissues, organelles and species (VANYUSHIN 2005). BOCKLANDT et al (2011) also found that the methylation level in individual genes substantially increased with the age of the organism.…”

Covalent genomic DNA modification patterns revealed by denaturing gradient gel blots

“…In vertebrates, widespread epigenetic modification of genomic DNA has been detected most commonly as methylation at the 5′ position of cytosine (5-methylcytosine) within symmetric 5′-CpG-3′ (CpG) dinucleotide sequences. In addition, 5-methylcytosines have been found within asymmetric, non-CpG sequences in mammals, including humans, as well as in plants (Clark et al, 1995;Wada et al, 2003;Inoue and Oishi, 2005;Vanyushin, 2005). In the genomes of bacteria, protists, fungi, and plants, N 6 -methyladenine is found at the internal adenine within 5′-TGATCA-3′ sequences (Vanyushin, 2005).…”

“…In addition, 5-methylcytosines have been found within asymmetric, non-CpG sequences in mammals, including humans, as well as in plants (Clark et al, 1995;Wada et al, 2003;Inoue and Oishi, 2005;Vanyushin, 2005). In the genomes of bacteria, protists, fungi, and plants, N 6 -methyladenine is found at the internal adenine within 5′-TGATCA-3′ sequences (Vanyushin, 2005). Although detection of N 6 -methyladenine in animal cells has not been reported, open reading frame DNA sequences homologous to bacterial adenine DNAmethyltransferases have been found in the genomes of insects, nematodes, and vertebrates, including humans, raising the possibility of the presence of adenine methylation in higher eukaryotes (Baniushin, 2005;Vanyushin, 2005).…”

“…In the genomes of bacteria, protists, fungi, and plants, N 6 -methyladenine is found at the internal adenine within 5′-TGATCA-3′ sequences (Vanyushin, 2005). Although detection of N 6 -methyladenine in animal cells has not been reported, open reading frame DNA sequences homologous to bacterial adenine DNAmethyltransferases have been found in the genomes of insects, nematodes, and vertebrates, including humans, raising the possibility of the presence of adenine methylation in higher eukaryotes (Baniushin, 2005;Vanyushin, 2005). In addition, post-translational modifications of histone proteins, including acetylation, phosphorylation, methylation, and ubiquitination, together with DNA methylation, modify chromatin structure and cause changes in patterns of gene expression (Cheung and Lau, 2005).…”