Histone methyltransferase

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Histone-lysine
N-methyltransferase
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EC no. 2.1.1.43
CAS no. 9055-08-7
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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. [1] 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. [2] [3] [4] In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group. [1] [5] [6] [7]
The genomic DNA of eukaryotes associates with histones to form chromatin. [8] The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. [9] Histone methylation is a principal epigenetic modification of chromatin [9] that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis. [2]

Contents

Front view of the human enzyme Histone Lysine N-Methyltransferase, H3 lysine-4 specific. Histone Methyltransferase, front view.tiff
Front view of the human enzyme Histone Lysine N-Methyltransferase, H3 lysine-4 specific.
Back view of the human enzyme Histone Lysine N-Methyltransferase, H3 lysine-4 specific. Active sites clearly visible. Histone Methyltransferase, back view.tiff
Back view of the human enzyme Histone Lysine N-Methyltransferase, H3 lysine-4 specific. Active sites clearly visible.

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:

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. [1]

Catalytic mechanism

In order for the reaction to proceed, S-Adenosyl methionine (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. [10] 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.

Active site of Histone Lysine N-Methyltransferase. Lysine residue (in yellow) and S-Adenosyl methionine (SAM) (in blue) clearly visible. Histone Methyltransferase, SAM and Lysine residue.tiff
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. [1] 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. [11] 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). [12] [13] [14] The second type (JBP1⧸PRMT5) produces monomethyl or symmetric dimethylarginine (Rme2s). [5] The third type (PRMT7) produces only monomethylated arginine. [15] The differences in methylation patterns of PRMTs arise from restrictions in the arginine binding pocket. [5]

Structure

The catalytic domain of PRMTs consists of a SAM binding domain and substrate binding domain (about 310 amino acids in total). [5] [6] [7] 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. [7]

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, [16] 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. [5] 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. [17]

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. [18] In contrast, methylation of histone residues H3K4, H3K36, and H3K79 is associated with transcriptionally active euchromatin. [2]

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. [15] 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. [18] 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. [18]

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. [18] [19] [20]

DNA repair

The methylation of histone lysine has an important role in choosing the pathway for repairing DNA double-strand breaks. [21] 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. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Histone</span> Protein family around which DNA winds to form nucleosomes

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

<span class="mw-page-title-main">Methyltransferase</span> Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

<span class="mw-page-title-main">Methyllysine</span> Derivative of the amino acid residue lysine

Methyllysine is derivative of the amino acid residue lysine where the sidechain ammonium group has been methylated one or more times.

<span class="mw-page-title-main">Histone-modifying enzymes</span> Type of 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 histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">EZH2</span> Protein-coding gene in the species Homo sapiens

Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.

<span class="mw-page-title-main">Tudor domain</span>

In molecular biology, a Tudor domain is a conserved protein structural domain originally identified in the Tudor protein encoded in Drosophila. The Tudor gene was found in a Drosophila screen for maternal factors that regulate embryonic development or fertility. Mutations here are lethal for offspring, inspiring the name Tudor, as a reference to the Tudor King Henry VIII and the several miscarriages experienced by his wives.

<span class="mw-page-title-main">SET domain</span>

The SET domain is a protein domain that typically has methyltransferase activity. It was originally identified as part of a larger conserved region present in the Drosophila Trithorax protein and was subsequently identified in the Drosophila Su(var)3-9 and 'Enhancer of zeste' proteins, from which the acronym SET is derived [Su(var)3-9, Enhancer-of-zeste and Trithorax].

Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number of different proteins. In biology, methyltransferases catalyze the methylation process, activated primarily by S-adenosylmethionine. Protein methylation has been most studied in histones, where the transfer of methyl groups from S-adenosyl methionine is catalyzed by histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

H3R42me is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the mono-methylation at the 42nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R17me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 17th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R26me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 26th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R8me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 8th arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

H3R2me2 is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates the di-methylation at the 2nd arginine residue of the histone H3 protein. In epigenetics, arginine methylation of histones H3 and H4 is associated with a more accessible chromatin structure and thus higher levels of transcription. The existence of arginine demethylases that could reverse arginine methylation is controversial.

References

  1. 1 2 3 4 Wood A, Shilatifard A (2004). "Posttranslational Modifications of Histones by Methylation". In Conaway JW, Conaway RC (eds.). Proteins in eukaryotic transcription. Advances in Protein Chemistry. Vol. 67. Amsterdam: Elsevier Academic Press. pp. 201–222. doi:10.1016/S0065-3233(04)67008-2. ISBN   0-12-034267-7. PMID   14969729.
  2. 1 2 3 Sawan C, Herceg Z (2010). "Histone Modifications and Cancer". In Ushijima T, Herceg Z (eds.). Epigenetics and Cancer, Part A, Volume 70. Advances in Genetics. Vol. 70. Boston: Academic Press. pp. 57–85. doi:10.1016/B978-0-12-380866-0.60003-4. ISBN   978-0-12-380866-0. PMID   20920745.
  3. ↑ Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, Zhang Y (June 2002). "Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain". Curr. Biol. 12 (12): 1052–8. doi:10.1016/S0960-9822(02)00901-6. PMID   12123582. S2CID   17263035.
  4. ↑ Ng HH, Feng Q, Wang H, Erdjument-Bromage H, Tempst P, Zhang Y, Struhl K (June 2002). "Lysine methylation within the globular domain of histone H3 by Dot1 is important for telomeric silencing and Sir protein association". Genes Dev. 16 (12): 1518–27. doi:10.1101/gad.1001502. PMC   186335 . PMID   12080090.
  5. 1 2 3 4 5 Branscombe TL, Frankel A, Lee JH, Cook JR, Yang Z, Pestka S, Clarke S (August 2001). "PRMT5 (Janus kinase-binding protein 1) catalyzes the formation of symmetric dimethylarginine residues in proteins". J. Biol. Chem. 276 (35): 32971–6. doi: 10.1074/jbc.M105412200 . PMID   11413150.
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  8. ↑ "Chromatin Network" . Retrieved 1 March 2012.
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  10. ↑ Trievel RC, Beach BM, Dirk LM, Houtz RL, Hurley JH (October 2002). "Structure and catalytic mechanism of a SET domain protein methyltransferase". Cell. 111 (1): 91–103. doi: 10.1016/S0092-8674(02)01000-0 . PMID   12372303.
  11. ↑ Min J, Feng Q, Li Z, Zhang Y, Xu RM (March 2003). "Structure of the catalytic domain of human DOT1L, a non-SET domain nucleosomal histone methyltransferase". Cell. 112 (5): 711–23. doi: 10.1016/S0092-8674(03)00114-4 . PMID   12628190.
  12. ↑ Chen D, Ma H, Hong H, Koh SS, Huang SM, Schurter BT, Aswad DW, Stallcup MR (June 1999). "Regulation of transcription by a protein methyltransferase". Science. 284 (5423): 2174–7. doi:10.1126/science.284.5423.2174. PMID   10381882.
  13. ↑ Gary JD, Lin WJ, Yang MC, Herschman HR, Clarke S (May 1996). "The predominant protein-arginine methyltransferase from Saccharomyces cerevisiae". J. Biol. Chem. 271 (21): 12585–94. doi: 10.1074/jbc.271.21.12585 . PMID   8647869.
  14. ↑ McBride AE, Weiss VH, Kim HK, Hogle JM, Silver PA (February 2000). "Analysis of the yeast arginine methyltransferase Hmt1p/Rmt1p and its in vivo function. Cofactor binding and substrate interactions". J. Biol. Chem. 275 (5): 3128–36. doi: 10.1074/jbc.275.5.3128 . PMID   10652296.
  15. 1 2 Blanc, Roméo S.; Richard, Stéphane (2017). "Arginine Methylation: The Coming of Age". Molecular Cell. 65 (1): 8–24. doi: 10.1016/j.molcel.2016.11.003 . PMID   28061334.
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  18. 1 2 3 4 5 Chen F, Kan H, Castranova V (2010). "Methylation of Lysine 9 of Histone H3: Role of Heterochromatin Modulation and Tumorigenesis". In Tollefsbol TO (ed.). Handbook of Epigenetics: The New Molecular and Medical Genetics. Boston: Academic Press. pp. 149–157. doi:10.1016/B978-0-12-375709-8.00010-1. ISBN   978-0-12-375709-8.
  19. ↑ Espino PS, Drobic B, Dunn KL, Davie JR (April 2005). "Histone modifications as a platform for cancer therapy". J. Cell. Biochem. 94 (6): 1088–102. doi: 10.1002/jcb.20387 . PMID   15723344.
  20. ↑ Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, Yagyu R, Nakamura Y (August 2004). "SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells". Nat. Cell Biol. 6 (8): 731–40. doi:10.1038/ncb1151. PMID   15235609. S2CID   13456531.
  21. ↑ Wei S, Li C, Yin Z, Wen J, Meng H, Xue L, Wang J (2018). "Histone methylation in DNA repair and clinical practice: new findings during the past 5-years". J Cancer. 9 (12): 2072–2081. doi:10.7150/jca.23427. PMC   6010677 . PMID   29937925.

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