Histone methyltransferases (HMT) are histone-modifying enzymes (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific (which can be SET (Su(var)3-9, Enhancer of Zeste, Trithorax) domain containing or non-SET domain containing) and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group. <br />
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis. The lysine chain then makes a nucleophilic attack on the methyl group on the sulfur atom of the SAM molecule, transferring the methyl group to the lysine side chain.
thumb|Active site of Histone Lysine N-Methyltransferase. Lysine residue (in yellow) and S-Adenosyl methionine (SAM) (in blue) clearly visible.
Non-SET domain-containing lysine-specific
Instead of SET, non-SET domain-containing histone methyltransferase utilizes the enzyme Dot1. Unlike the SET domain, which targets the lysine tail region of the histone, Dot1 methylates a lysine residue in the globular core of the histone, and is the only enzyme known to do so. Due to structural constraints, Dot1 is only able to methylate histone H3.
Arginine-specific
There are three different types of protein arginine methyltransferases (PRMTs) and three types of methylation that can occur at arginine residues on histone tails. The first type of PRMTs (PRMT1, PRMT3, CARM1⧸PRMT4, and Rmt1⧸Hmt1) produce monomethylarginine and asymmetric dimethylarginine (Rme2a). The second type (JBP1⧸PRMT5) produces monomethyl or symmetric dimethylarginine (Rme2s). The differences in methylation patterns of PRMTs arise from restrictions in the arginine binding pocket. which can then make a nucleophilic attack on the methyl group of SAM. Differences between the two types of PRMTs determine the next methylation step: either catalyzing the dimethylation of one nitrogen or allowing the symmetric methylation of both groups.
Role in gene regulation
Histone methylation plays an important role in epigenetic gene regulation. Methylated histones can either repress or activate transcription as different experimental findings suggest, depending on the site of methylation. For example, it is likely that the methylation of lysine 9 on histone H3 (H3K9me3) in the promoter region of genes prevents excessive expression of these genes and, therefore, delays cell cycle transition and/or proliferation. In recent years, epigenetic modification of the histone proteins, especially the methylation of the histone H3, in cancer development has been an area of emerging research. It is now generally accepted that in addition to genetic aberrations, cancer can be initiated by epigenetic changes in which gene expression is altered without genomic abnormalities. These epigenetic changes include loss or gain of methylations in both DNA and histone proteins.
DNA repair
The methylation of histone lysine has an important role in choosing the pathway for repairing DNA double-strand breaks. As an example, tri-methylated H3K36 is required for homologous recombinational repair, while dimethylated H4K20 can recruit the 53BP1 protein for repair by the pathway of non-homologous end joining.
Further research
Histone methyltransferase may be able to be used as biomarkers for the diagnosis and prognosis of cancers. Additionally, many questions still remain about the function and regulation of histone methyltransferases in malignant transformation of cells, carcinogenesis of the tissue, and tumorigenesis.