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Histone methyltransferases (HMT) are histone-modifying
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s (e.g., histone-lysine N-methyltransferases and histone-arginine N-methyltransferases), that
catalyze Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the transfer of one, two, or three methyl groups to lysine and arginine residues of
histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
s. 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 Domain may refer to: Mathematics *Domain of a function, the set of input values for which the (total) function is defined **Domain of definition of a partial function **Natural domain of a partial function **Domain of holomorphy of a function * Do ...
containing or non-SET domain containing) and arginine-specific. In both types of histone methyltransferases,
S-Adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
(SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form
chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...
. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.


Types

The class of lysine-specific histone methyltransferases is subdivided into SET domain-containing and non-SET domain-containing. As indicated by their monikers, these differ in the presence of a SET domain, which is a type of protein domain. Human genes encoding proteins with histone methyltransferase activity include: * ASH1L * DOT1L * EHMT1,
EHMT2 Euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a, is a histone methyltransferase enzyme that in humans is encoded by the ''EHMT2'' gene. G9a catalyzes the mono- and di-methylated states of histone H3 at lysine residue 9 ...
,
EZH1 #REDIRECT EZH1 {{R from other capitalization ...
,
EZH2 Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme ( EC 2.1.1.43) encoded by gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups ...
* MLL,
MLL2 Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferase ...
,
MLL3 Lysine N-methyltransferase 2C (KMT2C) also known as myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3) is an enzyme that in humans is encoded by the ''KMT2C'' gene. Function This gene is a member of the myeloid/lymphoid or mixed-linea ...
,
MLL4 Myeloid/lymphoid or mixed-lineage leukemia 4, also known as MLL4, is a human gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''b ...
,
MLL5 Lysine methyltransferase 2E is a protein that in humans is encoded by the gene. Function This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a protein with an N-terminal PHD zinc finger and a centr ...
*
NSD1 NSD1 (Nuclear receptor binding SET Domain Protein 1) is a transcription coregulator protein that encodes Histone Methyltransferase and is associated with Sotos syndrome and Weaver syndrome Weaver syndrome is a rare autosomal dominant genetic d ...
*
PRDM2 PR domain zinc finger protein 2 is a protein that in humans is encoded by the ''PRDM2'' gene. Function This tumor suppressor gene is a member of a nuclear histone/protein methyltransferase superfamily. It encodes a zinc finger protein that can ...
*
SET Set, The Set, SET or SETS may refer to: Science, technology, and mathematics Mathematics *Set (mathematics), a collection of elements *Category of sets, the category whose objects and morphisms are sets and total functions, respectively Electro ...
,
SETBP1 SET binding protein 1 is a protein that in humans is encoded by the SETBP1 gene. Gene The gene is located on Chromosome 18, specifically on the long (q) arm of the chromosome at position 12.3. This is also written as 18q12.3. Function The S ...
,
SETD1A SET domain containing protein 1A (SETD1A) is a protein that serves as a component of a histone methyltransferase (HMT) complex that produces mono-, di-, and trimethylated histone H3 at the lys4 residue ( K4). SETD1A is highly homologous with SETDB1 ...
, SETD1B,
SETD2 SET domain containing 2 is an enzyme that in humans is encoded by the ''SETD2'' gene. Function SETD2 protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active c ...
, SETD3, SETD4, SETD5,
SETD6 SET domain containing 6 is a protein in humans that is encoded by the SETD6 gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''b ...
, SETD7,
SETD8 N-lysine methyltransferase KMT5A is an enzyme that in humans is encoded by the ''KMT5A'' gene. The enzyme is a histone methyltransferase, SET domain-containing and lysine-specific. The enzyme transfers one methyl group to histone H4 lysine Ly ...
,
SETD9 Histone-lysine N-methyltransferase SETD7 is an enzyme that in humans is encoded by the ''SETD7'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning '' ...
,
SETDB1 Histone-lysine N-methyltransferase SETDB1 is an enzyme that in humans is encoded by the ''SETDB1'' gene. SETDB1 is also known as KMT1E or H3K9 methyltransferase ESET. Function The SET domain is a highly conserved, approximately 150-amino acid ...
, SETDB2 * SETMAR, SMYD1, SMYD2,
SMYD3 SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (myeloid-Nervy-DEAF-1) domain-containing protein 3 is a protein that in humans is encoded by the ''SMYD3'' gene. Function SMYD3 is a lysine methyltransferase which specific ...
,
SMYD4 SET and MYND domain-containing protein 4 is a protein that in humans is encoded by the ''SMYD4'' gene. Model organisms Model organisms have been used in the study of SMYD4 function. A conditional knockout mouse line, called ''Smyd4tm1a(EUCOMM)Wt ...
, SMYD5, SUV39H1, SUV39H2, KMT5B, SUV420H2


SET domain-containing lysine-specific


Structure

The structures involved in methyltransferase activity are the SET domain (composed of approximately 130 amino acids), the pre-SET, and the post-SET domains. The pre-SET and post-SET domains flank the SET domain on either side. The pre-SET region contains cysteine residues that form triangular zinc clusters, tightly binding the zinc atoms and stabilizing the structure. The SET domain itself contains a catalytic core rich in β-strands that, in turn, make up several regions of β-sheets. Often, the β-strands found in the pre-SET domain will form β-sheets with the β-strands of the SET domain, leading to slight variations to the SET domain structure. These small changes alter the target residue site specificity for methylation and allow the SET domain methyltransferases to target many different residues. This interplay between the pre-SET domain and the catalytic core is critical for enzyme function.


Catalytic mechanism

In order for the reaction to proceed,
S-Adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
(SAM) and the lysine residue of the substrate histone tail must first be bound and properly oriented in the catalytic pocket of the SET domain. Next, a nearby tyrosine residue deprotonates the ε-amino group of the lysine residue. 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.


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. A possible homolog of Dot1 was found in archaea which shows the ability to methylate archaeal histone-like protein in recent studies.


Structure

The N terminal of Dot1 contains the active site. A loop serving as the binding site for SAM links the N-terminal and the C-terminal domains of the Dot1 catalytic domain. The C-terminal is important for the substrate specificity and binding of Dot1 because the region carries a positive charge, allowing for a favorable interaction with the negatively charged backbone of DNA. 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 Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the ''PRMT1'' gene. The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4. Function ...
,
PRMT3 Protein arginine N-methyltransferase 3 is an enzyme that in humans is encoded by the ''PRMT3'' gene. Model organisms Model organisms have been used in the study of PRMT3 function. A conditional knockout mouse line, called ''Prmt3tm1a(EUCOM ...
,
CARM1 CARM1 (coactivator-associated arginine methyltransferase 1), also known as PRMT4 (protein arginine N-methyltransferase 4), is an enzyme () encoded by the gene found in human beings, as well as many other mammals. It has a polypeptide (L) chain t ...
⧸PRMT4, and Rmt1⧸Hmt1) produce monomethylarginine and asymmetric dimethylarginine (Rme2a). The second type (JBP1⧸ PRMT5) produces monomethyl or symmetric dimethylarginine (Rme2s). The third type (PRMT7) produces only monomethylated arginine. The differences in methylation patterns of PRMTs arise from restrictions in the arginine binding pocket.


Structure

The catalytic domain of PRMTs consists of a SAM binding domain and substrate binding domain (about 310 amino acids in total). Each PRMT has a unique N-terminal region and a catalytic core. The arginine residue and SAM must be correctly oriented within the binding pocket. SAM is secured inside the pocket by a hydrophobic interaction between an adenine ring and a phenyl ring of a phenylalanine.


Catalytic mechanism

A glutamate on a nearby loop interacts with nitrogens on the target arginine residue. This interaction redistributes the positive charge and leads to the deprotonation of one nitrogen group, 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. However, in both cases the proton stripped from the nitrogen is dispersed through a histidine–aspartate proton relay system and released into the surrounding matrix.


Role in gene regulation

Histone methylation plays an important role in epigenetic
gene regulation Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wi ...
. 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 contrast, methylation of histone residues H3K4, H3K36, and H3K79 is associated with transcriptionally active euchromatin. Depending on the site and symmetry of methylation, methylated arginines are considered activating (histone H4R3me2a, H3R2me2s, H3R17me2a, H3R26me2a) or repressive (H3R2me2a, H3R8me2a, H3R8me2s, H4R3me2s) histone marks. Generally, the effect of a histone methyltransferase on gene expression strongly depends on which histone residue it methylates. See Histone#Chromatin regulation.


Disease relevance

Abnormal expression or activity of methylation-regulating enzymes has been noted in some types of human cancers, suggesting associations between histone methylation and malignant transformation of cells or formation of tumors. 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. There is not yet compelling evidence that suggests cancers develop purely by abnormalities in histone methylation or its signaling pathways, however they may be a contributing factor. For example, down-regulation of methylation of lysine 9 on histone 3 (H3K9me3) has been observed in several types of human cancer (such as colorectal cancer, ovarian cancer, and lung cancer), which arise from either the deficiency of H3K9 methyltransferases or elevated activity or expression of H3K9 demethylases.


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 recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
al repair, while dimethylated H4K20 can recruit the
53BP1 Tumor suppressor p53-binding protein 1 also known as p53-binding protein 1 or 53BP1 is a protein that in humans is encoded by the ''TP53BP1'' gene. Clinical significance 53BP1 is underexpressed in most cases of triple-negative breast cancer. D ...
protein for repair by the pathway of
non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direc ...
.


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.


See also

*
Histone-Modifying Enzymes Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core hi ...
* Histone acetyltransferase (HAT) * Histone deacetylase (HDAC) * RNA polymerase control by chromatin structure * Histone methylation


References


Further reading

* *


External links


GeneReviews/NCBI/NIH/UW entry on Kleefstra Syndrome
* * {{DEFAULTSORT:Histone Methyltransferase EC 2.1.1 Epigenetics Methylation