Histone Lysine methyltransferases

Lysine methyltransferases are the most widely studied and classified writers. All of these enzymes contain the evolutionarily conserved catalytic SET [Su(var)3-9, Enhancer-of-zeste, Trithorax] domain. They catalyse the transfer of methyl groups from S-Adenosyl methionine (SAM) to e-amino group of target lysine residues by an SN-2 mechanism.

There are mainly 7 important families of methyltransferases known till date. These include EZ, SET1, SET2, SMYD, SUV39, SUV4-20, RIZ as main families and SET8/PR-SET7 and SET7/9 as other families. Each family has a characteristic domain associated with SET. It could be Pre-Set, Post-set, PHD, Tudor etc.

We found 30 unique SET domain containing proteins belonging to the above mentioned families and capable of histone methylation through literature. Histone marks created by these enzymes can either activate transcription (H3K4me) or repress transcription (H3K27me, H2K9me). Hence the activity of these enzymes together helps in creation of bivalent chromatin marks in order to keep genes in a poised state (activation/repression). They play important role in many cellular processes like DNA replication, cell cycle progression, cytokinesis, transcriptional regulation of Hox genes and tumour suppressor genes, DNA damage response, replication stress response, X chromosome inactivation, and energy homeostasis. Another significant contribution is the regulation of master regulators like p53 and components of NF-kB pathway. They are also involved in maintenance of chromatin structure by creating marks that recruit heterochromatin protein (HP1) in order to initiate the process of heterochromatinisation.

A large amount of literature supports the role of lysine methyltransferases in cancers. Either the expression of these proteins is altered or they undergo mutations. For example MLLs and NSDs have been heavily implicated in multiple cancers like breast, lung, colorectal, different types of blood and prostate cancers. These proteins are also involved in Sotos syndrome, Huntingtons disease, Wolf-Hirschhorn syndrome and Weaver syndrome.

Further reading: PMID: 12151224, PMID: 11893494, PMID: 17013555.

Cytogenetic map of Lysine methyltransferases coding genes
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Different histone Lysine methyltransferases
Enzyme (UniprotKB recommended name) Coding gene/s Site of histone modification
Histone-lysine N-methyltransferase EZH1EZH1H3K27me1, H3K27me2
Histone-lysine N-methyltransferase EZH2EZH2H3K27me1, H3K27me2, H3K27me3, H1K25me1
Histone-lysine N-methyltransferase MLLMLLH3K4me3
Histone-lysine N-methyltransferase MLL2MLL2
Histone-lysine N-methyltransferase MLL3MLL3H3K4me3
Histone-lysine N-methyltransferase MLL4UnknownH3K4me3
Histone-lysine N-methyltransferase MLL5MLL5
Histone-lysine N-methyltransferase NSD3WHSC1L1H3K4me2, H3K27me2, H3K27me3
Histone-lysine N-methyltransferase PRDM9PRDM9H3K4me3
Histone-lysine N-methyltransferase SETD1ASETD1AH3K4me3
Histone-lysine N-methyltransferase SETD1BSETD1BH3K4me3
Histone-lysine N-methyltransferase SETD2SETD2H3K36me3
Histone-lysine N-methyltransferase SETD7SETD7H3K4me1
Histone-lysine N-methyltransferase SETD8SETD8H4K20me1, H4K20me2
Histone-lysine N-methyltransferase SETDB1SETDB1H3K9me3
Histone-lysine N-methyltransferase SETDB2SETDB2H3K9me3
Histone-lysine N-methyltransferase SETMARSETMARH3K36me2
Histone-lysine N-methyltransferase SUV39H1SUV39H1H3K9me3
Histone-lysine N-methyltransferase SUV39H2SUV39H2H3K9me3
Histone-lysine N-methyltransferase SUV420H1SUV420H1H4K20me2, H4K20me3
Histone-lysine N-methyltransferase SUV420H2SUV420H2H4K20me2, H4K20me3
Histone-lysine N-methyltransferase, H3 lysine-36 and H4 lysine-20 specificNSD1H3K36me2, H4K20me2
Histone-lysine N-methyltransferase, H3 lysine-79 specificDOT1LH3K79me1, H3K79me2, H3K79me3
Histone-lysine N-methyltransferase, H3 lysine-9 specific 3EHMT2H3K9me1, H3K9me2, H3K27me1, H1K186me1, H1K25me1
Histone-lysine N-methyltransferase, H3 lysine-9 specific 5EHMT1H3K9me2, H3K27me1, H1K25me1, H1K186me1
N-lysine methyltransferase SMYD2SMYD2H3K36me2
PR domain zinc finger protein 2PRDM2H3K9me2
Probable histone-lysine N-methyltransferase ASH1LASH1LH3K36me1, H3K36me2
Probable histone-lysine N-methyltransferase NSD2WHSC1H3K36me3, H4K20me1, H4K20me3
SET and MYND domain-containing protein 3SMYD3H3K4me3