Eukaryotic DNA methylation: facts and problems

Abstract

Patterns of DNA methylation in complex genomes like those of mammalian cells have been viewed as indicators of different levels of genetic activities. It is as yet unknown how these complicated patterns are generated and maintained during cell replication. There is evidence from many different biological systems that the sequence‐specific methylation of promoters in higher eukaryotes is one of the important factors in controlling gene activity at a long‐term level. In general, the fifth nucleotide 5‐methyldeoxycytidine can be considered as a modulator of protein‐DNA interactions. The degree and direction of this modulation has to be assessed experimentally in each individual instance. The establishment of de novo patterns of DNA methylation is characterized by the gradual non‐random spreading of DNA methylation by an essentially unknown mechanism. In this review, some of the general concepts of DNA methylation in mammalian systems are presented, and research currently performed in the authors' laboratory has been summarized.

Modelling DNA Methylation Dynamics

“…The results consist of a range of distributions, which are analysed in relation to possible biological significance. The broad spectrum thus obtained, can be attributed to the self-adapting and dynamic nature of the human genome exhibited through events such as self mutations (mC to T, (Doerfler & Böhm, 2006)) or reassignment of DNA methylation patterns across different cells. This ability of cells to dynamically adapt to environmental stimulus by introducing molecular modifications or positive mutations, (which changes nucleotide distributions), is also referred to as "Phenotypic Plasticity".…”

“…The spread of DNA methylation in the genome is not randomly determined. Emerging evidence indicates that, although chromatin modeling factors, iRNA, histone modifications and even parental imprinting memory can influence methylation, the underlying genotype or DNA sequence has a stronger key role in enabling and propagating a spectrum of methylation patterns, (Doerfler & Böhm, 2006;Gertz et al, 2011). The nature of every biological cell is characterized by its preservation of the genetic and epigenetic contents also known as "dual inheritance" and in consequence it is of utmost importance to look at the underlying genetic pattern maps for further comprehension of the epigenetic phenomenon.…”

“…DNA Methylation was initially addressed as one of the most primitive mechanisms that organisms utilize to (a) protect genomic DNA and initiate the host resistance mechanism towards foreign DNA insertion and subsequently, (b) control gene expression, (Doerfler & Böhm, 2006). From an evolutionary point of view as well, the catalytic domain in the structure of the methylation enzymes across all organisms has been preserved to perform methyl group addition.…”

“…In humans, there are two ways by which DNA Methylation is established -(a)De novo methylation that establishes new DM patterns, (b) Maintenance methylation responsible for inheriting existing DM patterns. Within the family of methylating enzymes (DNMT), two types namely DNMT3a/b/L and DNMT1 establish DM patterns in these two ways, (Doerfler & Böhm, 2006). The De novo methylation process carried out by DNMT3a/b/L, is responsible for methylating embryonic cells which are totally erased of any previous DM patterns and methylated based on the DNA sequence contents.…”

“…DNA methylation refers to the modification of DNA by addition of a methyl group to the cytosine base, and is the most stable, heritable and well conserved epigenetic change. It is introduced and maintained, (Riggs & Xiong, 2004;Ushijima et al, 2003) by an enzyme family called DNA Methyl Transferases (DNMT), (Doerfler et al, 1990). Methyl-Cytosine or "mC", often referred to as the fifth type of nucleotide plays an extremely important role in gene expression and other cellular activities.…”