DNA Methylation

DNA Methylation:

DNA Methylation is one of the most commonly occurring epigenetic events taking place in the mammalian genome.

This change though heritable, is reversible, making it a therapeutic target. Methylation pattern is determined during embryo genesis and passed over to differentiating cells and tissues. DNA structure is maintained from generation to generation. This structure is modified by base methylation in nearly all cells and organisms.

The DNA of most organisms is modified by a post replicative process which results in three types of methylated bases in DNA:

C5-methylcytosine(5-mc)

N4 - Methyl cytosine}

N6- Methyladenine}  Wide spread in prokaryotes

This modification is called DNA methylation. DNA methylation is a covalent modification of DNA that does not change the DNA sequence, but has an influence on gene activity. It occurs in the cells of fungi, plants, non-vertebrates and vertebrates. In vertebrates, 3-6% of DNA cytosine is methylated. In plants you can see 30% of DNA cytosine is methylated. There is no methylation in many insects and single celled eukaryotes.

Addition of methyl group to C-5 position of cytosine residues. Most of the cytosine methylation occurs in the sequence context 5'CG3' occurs almost exclusively at cytosines that are followed immediately by a Guanine-CpG Dinucleotide.

Mechanism:

Methyl group are transferred from S-adenosyl methionine in a reaction catalyses by a DNA methyl transferases(DNMT) or methylases. SAM is then converted to SAH(S-adenosyl homocysteine)

Enzyme involved in DNA methylation

1. DNA Methyl Transferase(DNMTs)
2. DNMTs catalyze this reaction at different times during the cell cycle.
3. In mammels, a) DNMT1- Maintenance methylase  b) DNMT2  c) DNMT 3a and DNMT 3b- de novo methylases
4. DNMT 3L

DNMT1:

• Maintains the pattern of DNA methylation after DNA replication.
• Requires a hemi-methylated DNA substrate and will faithfully reproduce the pattern of DNA methylation on the newly synthesized strands.
• DNA methylation- 'an automatic semi conservative mechanism'.

DNMT 3a and DNMT 3b:

• Will add methyl groups to CG dinucleotides which are previously unmethylated on both the strands.
• Re-establish the methylation pattern.