DNA methylation is the process through which a methyl group is added to DNA nucleotides. The most common form of this occurs at the 5-carbon position of cytosine (5 methylcytosine or 5mC). DNA methylation can stably alter the gene expression of a cell, which may direct processes like stem cell differentiation and genomic imprinting.
DNA methylation 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. DNA methylation has been demonstrated as a vital contributor to a wide range of cellular processes, and aberrant methylation patterns have been liked to several human diseases.
Key Players in DNA Methylation
Ten-eleven Translocation (TET) Enzymes: The discovery of Ten-eleven translocation (TET) enzymes provide a mechanistic basis for a mostly hypothetical pathway, active DNA demethylation. The enzymes are named for a common translocation in cancers.
5-methylcytosine (5mC): Unless you’ve been living under a rock, or maybe under a CpG island, then you’ve heard of 5-methylcytosine (5mC). 5mC is the normal cytosine nucleotide in DNA that has been modified by the addition of a methyl group to its 5th carbon. The role of this mark is so distinct that many consider 5mC to be the “5th base” of DNA.
5-hydroxymethylcytosine (5hmC): Has the potential to greatly deepen our understanding of epigenetics of the brain and development. 5hmC is the first oxidative product in the active demethylation of 5-methylcytosine (5mC). The three Ten-eleven translocation (TET) enzymes oxidize each step in the demethylation of 5mC. 5mC is first converted to 5hmC, then 5-formylcytosine (5fC), then 5-carboxylcytosine (5caC)
5-formylcytosine (5fC): One of the oxidized derivatives of 5-methylcytosine (5mC) demethylation. 5mC is oxidized to 5-hydroxymethylcytosine (5hmC) which is then oxidized to 5fC.
5-carboxylcytosine (5caC): The final oxidized derivative of 5-methylcytosine (5mC). 5mC is oxidized to 5-hydroxymethylcytosine (5hmC) which is then oxidized to 5-formylcytosine (5fC) then 5caC. Each of these oxidation steps are catalyzed by the Ten-Eleven Translocation (TET) family of enzymes. 5fC can then be further oxidized to 5-carboxylcytosine (5caC) by TET
DNA Methyltransferases: DNMTs are the writers of the epigenome. DNMTs are a highly conserved family of proteins present in nearly all life on earth. In mammals, there are 3 major DNMTs: DNMT1, DNMT3a and DNMT3b.
N6-Methyladenosine: m6A refers to methylation of the adenosine base at the nitrogen-6 position. The existence of this modification has been known for some time. It is very common in prokaryotic genomes, but has not been found in appreciable amounts in eukaryotic DNA. It is very common however in eukaryotic messenger RNA (mRNA).