DNA (cytosine-5)-methyltransferase 3A

Last updated
DNMT3A
Protein DNMT3A PDB 2QRV.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DNMT3A , DNMT3A2, M.HsaIIIA, TBRS, DNA (cytosine-5-)-methyltransferase 3 alpha, DNA methyltransferase 3 alpha, HESJAS
External IDs OMIM: 602769 MGI: 1261827 HomoloGene: 7294 GeneCards: DNMT3A
Orthologs
SpeciesHumanMouse
Entrez

1788

13435

Ensembl

ENSG00000119772

ENSMUSG00000020661

UniProt

Q9Y6K1

O88508

RefSeq (mRNA)

NM_001271753
NM_007872
NM_153743

RefSeq (protein)

NP_001258682
NP_031898
NP_714965

Location (UCSC) Chr 2: 25.23 – 25.34 Mb Chr 12: 3.86 – 3.96 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

DNA (cytosine-5)-methyltransferase 3A (DNMT3A) is an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, a process called DNA methylation. The enzyme is encoded in humans by the DNMT3A gene. [5] [6]

This enzyme is responsible for de novo DNA methylation. Such function is to be distinguished from maintenance DNA methylation which ensures the fidelity of replication of inherited epigenetic patterns. DNMT3A forms part of the family of DNA methyltransferase enzymes, which consists of the protagonists DNMT1, DNMT3A and DNMT3B. [5] [6]

While de novo DNA methylation modifies the information passed on by the parent to the progeny, it enables key epigenetic modifications essential for processes such as cellular differentiation and embryonic development, transcriptional regulation, heterochromatin formation, X-inactivation, imprinting and genome stability. [7]

DNMT3a is the gene most commonly found mutated in clonal hematopoiesis, a common aging-related phenomenon in which hematopoietic stem cells (HSCs) or other early blood cell progenitors contribute to the formation of a genetically distinct subpopulation of blood cells. [8] [9] [10]

Gene

DNMT3A is a 130 kDa protein encoded by 23 exons found on chromosome 2p23 in humans. [11] There exists a 98% homology between human and murine homologues. [6] DNMT3A is widely expressed among mammals. [12]

There are two main protein isoforms, DNMT3A1 and DNMT3A2 with molecular weights of about 130 kDa and 100 kDa, respectively. The DNMT3A2 protein, which lacks the N-terminal region of DNMT3A1, is encoded by a transcript initiated from a downstream promoter. [13] These isoforms exist in different cell types. [14] When originally established, [13] DNMT3A2 was found to be highly expressed in testis, ovary, spleen, and thymus. It was more recently shown to be inducibly expressed in brain hippocampus [15] and needed in the hippocampus when establishing memory. [16] DNMT3A2 is also upregulated in the nucleus accumbens shell in response to cocaine. [17]

Protein structure

DNMT3A consists of three major protein domains: the Pro-Trp-Trp-Pro (PWWP) domain, the ATRX-DNMT3-DNMT3L (ADD) domain and the catalytic methyltransferase domain.

This illustrates 5 isoforms of DNMT3A showing the locations of the PWWP domain, the ADD domain and the catalytic or catalytic-like domains. Simplified domains of DNMT3A isoforms.jpg
This illustrates 5 isoforms of DNMT3A showing the locations of the PWWP domain, the ADD domain and the catalytic or catalytic-like domains.

The structures of DNMT3A1 and DNMT3A2 have analogies with the structure of DNMT3B1 and also with the two accessory proteins DNMT3B3 and DNMT3L (see Figure of simplified domains of DNMT3A isoforms). The two accessory proteins stimulate de novo methylation by each of their interactions with the three isoforms that have a functional catalytic domain. In general, all DNMTs require accessory proteins for their biological function. [18]

The PWWP motif is within an about 100 amino acid domain that has one area with a significant amount of basic residues (lysines and arginines), giving a positively charged surface that can bind to DNA. A separate region of the PWWP domain can bind to histone methyl-lysines through a hydrophobic pocket that includes the PWWP motif itself. [19] [20]

The ADD domain of DNMT3A is composed of an N-terminal GATA-like zinc finger, a PHD finger and a C-terminal alpha helix, which, together, are arranged into a single globular fold. This domain can act as a reader that specifically binds to histone H3 that is unmethylated at lysine 4 (H3K4me0). [21] The ADD domain serves as an inhibitor of the methyltransferase domain until DNMT3A binds to the unmodified lysine 4 of histone 3 (H3K4me0) for its de novo methylating activity. [14] DNMT3A thus seems to have an inbuilt control mechanism targeting DNA for methylation only at histones that are unmethylated at histone 3 with the lysine at the 4th position from the amino end being un-methylated.

The catalytic domain (the methyltransferase domain) is highly conserved, even among prokaryotes. [22]

DNMTs such as DNMT3A2, with a functioning catalytic domain, require an accessory protein, such as DNMT3B3 without a functioning catalytic domain, for methylating activity in vivo, as in the heterotetrameric structure shown here. Heterotetramer of DNMTs 3A2 and 3B3 and its interactions with nucleosome and linker DNA.jpg
DNMTs such as DNMT3A2, with a functioning catalytic domain, require an accessory protein, such as DNMT3B3 without a functioning catalytic domain, for methylating activity in vivo, as in the heterotetrameric structure shown here.

The three DNA methyltransferases (DNMT3A1, DNMT3A2 and DNMT3B) catalyze reactions placing a methyl group onto a cytosine, usually at a CpG site in DNA. [23] The accompanying Figure shows a methyltransferase complex containing DNMT3A2. These enzymes, to be effective, must act in conjunction with an accessory protein (e.g. DNMT3B3, DNMT3L, or others). [24] [25] [26] Two accessory proteins (which have no catalytic activity), complexed to two DNMTs with a catalytic domain, occur as a heterotetramer (see Figure). These heterotetramers occur in the order: accessory protein-catalytic protein-catalytic protein-accessory protein. The particular complex shown in the Figure illustrates the heterotetramer formed by catalytic protein DNMT3A2 and accessory protein DNMT3B3. One accessory protein of the complex binds to an acidic patch on the nucleosome core (see top 3B3 in Figure). The connection of one accessory protein to the nucleosome orients the heterotetramer. The orientation places the first catalytic DNMT (closest to the accessory protein connected to the nucleosome) in an intermediate position (not close to the linker DNA). The second catalytic DNMT (lower 3A2 in Figure) is placed at the linker DNA. Methylations can take place within this linker DNA (as shown in the Figure) but not on any DNA wrapped around the nucleosome core.

As shown by Manzo et al., [27] there are both specific individual binding sites for the three catalytic DNMTs (3A1, 3A2 and 3B3) as well as overlapping binding sites of these enzymes. There are 28 million CpG sites in the human genome. [28] Many of these CpGs are located within CpG islands (regions of DNA) of relatively high density of CpG sites. [28] Of these regions, there are 3,970 regions exclusively enriched for DNMT3A1, 3,838 regions for DNMT3A2 and 3,432 regions for DNMT3B, and there are sites that are shared between the de novo DNMT proteins. [27] In addition, whether the DNA methyltransferase (DNMT3A1, DNMT3A2 or DNMT3B) acts on an available CpG site depends on the sequence flanking the CpG site within the linker DNA. [26]

Function

DNMT1 is responsible for maintenance DNA methylation while DNMT3A and DNMT3B carry out both maintenance – correcting the errors of DNMT1 – and de novo DNA methylation. After DNMT1 knockout in human cancer cells, these cells were found to retain their inherited methylation pattern, [29] which suggests maintenance activity by the expressed DNMT3s. DNMT3s show equal affinity for unmethylated and hemimethylated DNA substrates [29] while DNMT1 has a 10-40 fold preference for hemimethylated DNA. [30] [31] The DNMT3s can bind to both forms and hence potentially do both maintenance and de novo modifications.

De novo methylation is the main recognized activity of DNMT3A, which is essential for processes such as those mentioned in the introductory paragraphs. Genetic imprinting prevents parthenogenesis in mammals, [32] and hence forces sexual reproduction and its multiple consequences on genetics and phylogenesis. DNMT3A is essential for genetic imprinting. [33]

Research on long-term memory storage in humans indicates that memory is maintained by DNA methylation, [34] Rats in which a new, strong long-term memory is induced due to contextual fear conditioning have reduced expression of about 1,000 genes and increased expression of about 500 genes in the hippocampus region of the brain. These changes occur 24 hours after training. At this point, there is modified expression of 9.17% of the rat hippocampal genome. Reduced expression of genes is associated with de novo methylations of the genes. [35]

Animal studies

In mice, this gene has shown reduced expression in ageing animals causes cognitive long-term memory decline. [15]

In Dnmt3a-/- mice, many genes associated with HSC self-renewal increase in expression and some fail to be appropriately repressed during differentiation. [36] This suggests abrogation of differentiation in hematopoietic stem cells (HSCs) and an increase in self-renewal cell-division instead. Indeed, it was found that differentiation was partially rescued if Dnmt3a-/- HSCs experienced an additional Ctnb1 knockdown – Ctnb1 codes for β-catenin, which participates in self-renewal cell division. [14]

Clinical relevance

This gene is frequently mutated in cancer, being one of 127 frequently mutated genes identified in the Cancer Genome Atlas project [37] DNMT3A mutations were most commonly seen in acute myeloid leukaemia (AML) where they occurred in just over 25% of cases sequenced. These mutations most often occur at position R882 in the protein and this mutation may cause loss of function. [38] DNMT3A mutations are associated with poor overall survival, suggesting that they have an important common effect on the potential of AML cells to cause lethal disease. [39] It has also been found that DNMT3A-mutated cell lines exhibit transcriptome instability, in that they have much more erroneous RNA splicing as compared to their isogenic wildtype counterparts. [40] Mutations in this gene are also associated with Tatton-Brown–Rahman syndrome, an overgrowth disorder.

Interactions

DNMT3A has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Epigenetics</span> Study of DNA modifications that do not change its sequence

In biology, epigenetics is the study of heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" the traditional genetic mechanism of inheritance. Epigenetics usually involves a change that is not erased by cell division, and affects the regulation of gene expression. Such effects on cellular and physiological phenotypic traits may result from environmental factors, or be part of normal development. They can lead to cancer.

<span class="mw-page-title-main">5-Methylcytosine</span> Chemical compound which is a modified DNA base

5-Methylcytosine is a methylated form of the DNA base cytosine (C) that regulates gene transcription and takes several other biological roles. When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered. 5-Methylcytosine is incorporated in the nucleoside 5-methylcytidine.

<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins produce messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

<span class="mw-page-title-main">DNA methyltransferase</span> Class of enzymes

In biochemistry, the DNA methyltransferase family of enzymes catalyze the transfer of a methyl group to DNA. DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.

<span class="mw-page-title-main">Histone methyltransferase</span> Histone-modifying enzymes

Histone methyltransferases (HMT) are histone-modifying enzymes, 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 and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
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. 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.

In molecular biology and genetics, transcriptional regulation is the means by which a cell regulates the conversion of DNA to RNA (transcription), thereby orchestrating gene activity. A single gene can be regulated in a range of ways, from altering the number of copies of RNA that are transcribed, to the temporal control of when the gene is transcribed. This control allows the cell or organism to respond to a variety of intra- and extracellular signals and thus mount a response. Some examples of this include producing the mRNA that encode enzymes to adapt to a change in a food source, producing the gene products involved in cell cycle specific activities, and producing the gene products responsible for cellular differentiation in multicellular eukaryotes, as studied in evolutionary developmental biology.

<span class="mw-page-title-main">DNA methylation</span> Biological process

DNA methylation is a biological process by which methyl groups are added to the DNA molecule. Methylation can change the activity of a DNA segment without changing the sequence. When located in a gene promoter, DNA methylation typically acts to repress gene transcription. In mammals, DNA methylation is essential for normal development and is associated with a number of key processes including genomic imprinting, X-chromosome inactivation, repression of transposable elements, aging, and carcinogenesis.

<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.

<span class="mw-page-title-main">DNMT1</span> Protein-coding gene in the species Homo sapiens

DNA (cytosine-5)-methyltransferase 1(Dnmt1) is an enzyme that catalyzes the transfer of methyl groups to specific CpG sites in DNA, a process called DNA methylation. In humans, it is encoded by the DNMT1 gene. Dnmt1 forms part of the family of DNA methyltransferase enzymes, which consists primarily of DNMT1, DNMT3A, and DNMT3B.

<span class="mw-page-title-main">DNMT3B</span> Protein-coding gene in the species Homo sapiens

DNA (cytosine-5)-methyltransferase 3 beta, is an enzyme that in humans in encoded by the DNMT3B gene. Mutation in this gene are associated with immunodeficiency, centromere instability and facial anomalies syndrome.

<span class="mw-page-title-main">SUV39H1</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase SUV39H1 is an enzyme that in humans is encoded by the SUV39H1 gene.

<span class="mw-page-title-main">DNMT3L</span> Protein-coding gene in the species Homo sapiens

DNA (cytosine-5)-methyltransferase 3-like is an enzyme that in humans is encoded by the DNMT3L gene.

<span class="mw-page-title-main">DNA demethylation</span> Removal of a methyl group from one or more nucleotides within a DNA molecule.

For molecular biology in mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequence or, in replicating cells, by preventing addition of methyl groups to DNA so that the replicated DNA will largely have cytosine in the DNA sequence.

<span class="mw-page-title-main">EHMT1</span> Protein-coding gene in the species Homo sapiens

Euchromatic histone-lysine N-methyltransferase 1, also known as G9a-like protein (GLP), is a protein that in humans is encoded by the EHMT1 gene.

While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications have been shown to play an important role in learning and memory.

Embryonic stem cells are capable of self-renewing and differentiating to the desired fate depending on their position in the body. Stem cell homeostasis is maintained through epigenetic mechanisms that are highly dynamic in regulating the chromatin structure as well as specific gene transcription programs. Epigenetics has been used to refer to changes in gene expression, which are heritable through modifications not affecting the DNA sequence.

Epigenetic regulation of neurogenesis is the role that epigenetics plays in the regulation of neurogenesis.

Neuroepigenetics is the study of how epigenetic changes to genes affect the nervous system. These changes may effect underlying conditions such as addiction, cognition, and neurological development.

<span class="mw-page-title-main">GLAD-PCR assay</span>

Glal hydrolysis and Ligation Adapter Dependent PCR assay is the novel method to determine R(5mC)GY sites produced in the course of de novo DNA methylation with DNMTЗA and DNMTЗB DNA methyltransferases. GLAD-PCR assay do not require bisulfite treatment of the DNA.

<span class="mw-page-title-main">TET enzymes</span> Family of translocation methylcytosine dioxygenases

The TET enzymes are a family of ten-eleven translocation (TET) methylcytosine dioxygenases. They are instrumental in DNA demethylation. 5-Methylcytosine is a methylated form of the DNA base cytosine (C) that often regulates gene transcription and has several other functions in the genome.

References

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