DNA Methylation

DNA methylation is a process by which methyl groups are added to the DNA molecule. It is an epigenetic mechanism that occurs by the addition of a methyl (-CH3) group to DNA, thereby often modifying the function of the genes and affecting gene expression.

The most widely characterized DNA methylation process is the covalent addition of the methyl group at the 5-carbon of the cytosine ring resulting in 5-methylcytosine (5-mC), also informally known as the “fifth base” of DNA.

These methyl groups project into the major groove of DNA and inhibits transcription. In human DNA, 5-methylcytosine is found in approximately 1.5% of genomic DNA.

It is typically removed during zygote formation and then re-established in the embryo at approximately the time of implantation.

It is the basis of chromatin structure and usually is found in a CpG dinucleotide context. Research has shown that methylation plays a crucial role in the regulation of gene expression and that these modifications tend to occur at specific locations within the genomes of different species.

It has been demonstrated as a vital contributor to a wide range of cellular processes, and aberrant methylation patterns have been linked to several human diseases.

Historically, it was discovered in mammals as early as DNA was identified as the genetic material. In 1948, Rollin Hotchkiss first discovered modified cytosine in preparation of calf thymus using paper chromatography.

It was hypothesized that this fraction was 5-methylcytosine (5mC) because it separated from cytosine in a manner that was similar to the way that thymine (also known as methyl uracil) separated from uracil, and he further suggested that this modified cytosine existed naturally in DNA.

Although many researchers proposed that it might regulate gene expression, it was not until the 1980s that several studies demonstrated that it was involved in gene regulation and cell differentiation.

It is now well recognized that, in concert with other regulators, it is a major epigenetic factor influencing gene activities.


Although virtually all cells in an organism contain the same genetic information, not all genes are expressed simultaneously by all cell types.

In a broader sense, epigenetic mechanisms mediate the diversified gene expression profiles in a variety of cells and tissues in multicellular organisms.

Once such a major epigenetic mechanism that involves direct chemical modification to the DNA is called DNA methylation.

During development, the pattern of DNA methylation in the genome changes as a result of a dynamic process involving both de novo DNA methylation and demethylation.

As a consequence, differentiated cells develop a stable and unique DNA methylation pattern that regulates tissue-specific gene transcription.


Most DNA methylation is essential for normal development.

It plays a very important role in a number of key processes including genomic imprinting, X-chromosome inactivation, and suppression of repetitive element transcription and transposition and, when dysregulated, contributes to diseases like cancer.

DNA methylation in different genomic regions may exert different influences on gene activities based on the underlying genetic sequence.


The addition of methyl groups is controlled at several different levels in cells and is carried out by a family of enzymes called DNA methyltransferases (DNMTs).

Three DNMTs (DNMT1, DNMT3a, and DNMT3b) are required for the establishment and maintenance of DNA methylation patterns.

Two additional enzymes (DNMT2 and DNMT3L) may also have more specialized but related functions.