5-Methylcytosine

Last updated
5-Methylcytosine
5-Methylcytosine.svg
Names
Preferred IUPAC name
4-Amino-5-methylpyrimidin-2(1H)-one
Identifiers
3D model (JSmol)
3DMet
120387
ChEBI
ChemSpider
ECHA InfoCard 100.008.236 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 209-058-3
KEGG
MeSH 5-Methylcytosine
PubChem CID
UNII
  • InChI=1S/C5H7N3O/c1-3-2-7-5(9)8-4(3)6/h2H,1H3,(H3,6,7,8,9) Yes check.svgY
    Key: LRSASMSXMSNRBT-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C5H7N3O/c1-3-2-7-5(9)8-4(3)6/h2H,1H3,(H3,6,7,8,9)
    Key: LRSASMSXMSNRBT-UHFFFAOYAO
  • O=C1/N=C\C(=C(\N)N1)C
  • Cc1cnc(=O)[nH]c1N
Properties
C5H7N3O
Molar mass 125.131 g·mol−1
Hazards
GHS labelling:
GHS-pictogram-exclam.svg
Warning
H317, H319
P261, P264, P272, P280, P302+P352, P305+P351+P338, P321, P333+P313, P337+P313, P363, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

5-Methylcytosine is a methylated form of the DNA base cytosine (C) that regulates gene transcription and takes several other biological roles. [1] When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered (the study of this is part of the field of epigenetics). 5-Methylcytosine is incorporated in the nucleoside 5-methylcytidine.

Contents

In 5-methylcytosine, a methyl group is attached to the 5th atom in the 6-atom ring, counting counterclockwise from the NH-bonded nitrogen at the six o'clock position. This methyl group distinguishes 5-methylcytosine from cytosine.

Discovery

While trying to isolate the bacterial toxin responsible for tuberculosis, W.G. Ruppel isolated a novel nucleic acid named tuberculinic acid in 1898 from Tubercle bacillus . [2] The nucleic acid was found to be unusual, in that it contained in addition to thymine, guanine and cytosine, a methylated nucleotide. In 1925, Johnson and Coghill successfully detected a minor amount of a methylated cytosine derivative as a product of hydrolysis of tuberculinic acid with sulfuric acid. [3] [4] This report was severely criticized because their identification was based solely on the optical properties of the crystalline picrate, and other scientists failed to reproduce the same result. [5] But its existence was ultimately proven in 1948, when Hotchkiss separated the nucleic acids of DNA from calf thymus using paper chromatography, by which he detected a unique methylated cytosine, quite distinct from conventional cytosine and uracil. [6] After seven decades, it turned out that it is also a common feature in different RNA molecules, although the precise role is uncertain. [7]

In vivo

The function of this chemical varies significantly among species: [8]

While spontaneous deamination of cytosine forms uracil, which is recognized and removed by DNA repair enzymes, deamination of 5-methylcytosine forms thymine. This conversion of a DNA base from cytosine (C) to thymine (T) can result in a transition mutation. [11] In addition, active enzymatic deamination of cytosine or 5-methylcytosine by the APOBEC family of cytosine deaminases could have beneficial implications on various cellular processes as well as on organismal evolution. [12] The implications of deamination on 5-hydroxymethylcytosine, on the other hand, remains less understood.

In vitro

The NH2 group can be removed (deamination) from 5-methylcytosine to form thymine with use of reagents such as nitrous acid; cytosine deaminates to uracil (U) under similar conditions.[ citation needed ]

Deamination of 5-methylcytosine to thymine Deamination 5-Methylcytosine to Thymine.svg
Deamination of 5-methylcytosine to thymine

5-methylcytosine is resistant to deamination by bisulfite treatment, which deaminates cytosine residues. This property is often exploited to analyze DNA cytosine methylation patterns with bisulfite sequencing. [13]

Addition and regulation with DNMTs (Eukaryotes)

5mC marks are placed on genomic DNA via DNA methyltransferases (DNMTs). There are 5 DNMTs in humans: DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L, and in algae and fungi 3 more are present (DNMT4, DNMT5, and DNMT6). [14] DNMT1 contains the replication foci targeting sequence (RFTS) and the CXXC domain which catalyze the addition of 5mC marks. RFTS directs DNMT1 to loci of DNA replication to assist in the maintenance of 5mC on daughter strands during DNA replication, whereas CXXC contains a zinc finger domain for de novo addition of methylation to the DNA. [15] DNMT1 was found to be the predominant DNA methyltransferase in all human tissue. [16] Primarily, DNMT3A and DNMT3B are responsible for de novo methylation, and DNMT1 maintains the 5mC mark after replication. [1] DNMTs can interact with each other to increase methylating capability. For example, 2 DNMT3L can form a complex with 2 DNMT3A to improve interactions with the DNA, facilitating the methylation. [17] Changes in the expression of DNMT results in aberrant methylation. Overexpression produces increased methylation, whereas disruption of the enzyme decreased levels of methylation. [16]

Addition of methyl group to cytosine DNMT reaction mechanism.tif
Addition of methyl group to cytosine

The mechanism of the addition is as follows: first a cysteine residue on the DNMT's PCQ motif creates a nucleophillic attack at carbon 6 on the cytosine nucleotide that is to be methylated. S-Adenosylmethionine then donates a methyl group to carbon 5. A base in the DNMT enzyme deprotonates the residual hydrogen on carbon 5 restoring the double bond between carbon 5 and 6 in the ring, producing the 5-methylcytosine base pair. [15]

Demethylation

After a cytosine is methylated to 5mC, it can be reversed back to its initial state via multiple mechanisms. Passive DNA demethylation by dilution eliminates the mark gradually through replication by a lack of maintenance by DNMT. In active DNA demethylation, a series of oxidations converts it to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), and the latter two are eventually excised by thymine DNA glycosylase (TDG), followed by base excision repair (BER) to restore the cytosine. [1] TDG knockout produced a 2-fold increase of 5fC without any statistically significant change to levels of 5hmC, indicating 5mC must be iteratively oxidized at least twice before its full demethylation. [18] The oxidation occurs through the TET (Ten-eleven translocation) family dioxygenases (TET enzymes) which can convert 5mC, 5hmC, and 5fC to their oxidized forms. However, the enzyme has the greatest preference for 5mC and the initial reaction rate for 5hmC and 5fC conversions with TET2 are 4.9-7.6 fold slower. [19] TET requires Fe(II) as cofactor, and oxygen and α-ketoglutarate (α-KG) as substrates, and the latter substrate is generated from isocitrate by the enzyme isocitrate dehydrogenase (IDH). [20] Cancer however can produce 2-hydroxyglutarate (2HG) which competes with α-KG, reducing TET activity, and in turn reducing conversion of 5mC to 5hmC. [21]

Role in humans

In cancer

In cancer, DNA can become both overly methylated, termed hypermethylation, and under-methylated, termed hypomethylation. [22] CpG islands overlapping gene promoters are de novo methylated resulting in aberrant inactivation of genes normally associated with growth inhibition of tumors (an example of hypermethylation). [23] Comparing tumor and normal tissue, the former had elevated levels of the methyltransferases DNMT1, DNMT3A, and mostly DNMT3B, all of which are associated with the abnormal levels of 5mC in cancer. [16] Repeat sequences in the genome, including satellite DNA, Alu, and long interspersed elements (LINE), are often seen hypomethylated in cancer, resulting in expression of these normally silenced genes, and levels are often significant markers of tumor progression. [22] It has been hypothesized that there a connection between the hypermethylation and hypomethylation; over activity of DNA methyltransferases that produce the abnormal de novo 5mC methylation may be compensated by the removal of methylation, a type of epigenetic repair. However, the removal of methylation is inefficient resulting in an overshoot of genome-wide hypomethylation. The contrary may also be possible; over expression of hypomethylation may be silenced by genome-wide hypermethylation. [22] Cancer hallmark capabilities are likely acquired through epigenetic changes that alter the 5mC in both the cancer cells and in surrounding tumor-associated stroma within the tumor microenvironment. [24] The anticancer drug Cisplatin has been reported to react with 5mC. [25]

As a biomarker of aging

"Epigenetic age" refers to the connection between chronological age and levels of DNA methylation in the genome. [26] Coupling the levels of DNA methylation, in specific sets of CpGs called "clock CpGs", with algorithms that regress the typical levels of collective genome-wide methylation at a given chronological age, allow for epigenetic age prediction. During youth (0–20 years old), changes in DNA methylation occur at a faster rate as development and growth progresses, and the changes begin to slow down at older ages. Multiple epigenetic age estimators exist. Horvath's clock measures a multi-tissue set of 353 CpGs, half of which positively correlate with age, and the other half negatively, to estimate the epigenetic age. [27] Hannum's clock utilizes adult blood samples to calculate age based on an orthogonal basis of 71 CpGs. [28] Levine's clock, known as DNAm PhenoAge, depends on 513 CpGs and surpasses the other age estimators in predicting mortality and lifespan, yet displays bias with non-blood tissues. [29] There are reports of age estimators with the methylation state of only one CpG in the gene ELOVL2. [30] Estimation of age allows for prediction lifespan through expectations of age related conditions that individuals may be subject to based on their 5mC methylation markers.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Cytosine</span> Chemical compound in nucleic acids

Cytosine is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine. It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached. The nucleoside of cytosine is cytidine. In Watson-Crick base pairing, it forms three hydrogen bonds with guanine.

<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">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">CpG site</span> Region of often-methylated DNA with a cytosine followed by a guanine

The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG islands.

<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">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.

In biology, reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development or in cell culture. Such control is also often associated with alternative covalent modifications of histones.

<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">Bisulfite sequencing</span> Lab procedure detecting 5-methylcytosines in DNA

Bisulfitesequencing (also known as bisulphite sequencing) is the use of bisulfite treatment of DNA before routine sequencing to determine the pattern of methylation. DNA methylation was the first discovered epigenetic mark, and remains the most studied. In animals it predominantly involves the addition of a methyl group to the carbon-5 position of cytosine residues of the dinucleotide CpG, and is implicated in repression of transcriptional activity.

<span class="mw-page-title-main">DNA (cytosine-5)-methyltransferase 3A</span> Protein-coding gene in the species Homo sapiens

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.

<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.

Methylated DNA immunoprecipitation is a large-scale purification technique in molecular biology that is used to enrich for methylated DNA sequences. It consists of isolating methylated DNA fragments via an antibody raised against 5-methylcytosine (5mC). This technique was first described by Weber M. et al. in 2005 and has helped pave the way for viable methylome-level assessment efforts, as the purified fraction of methylated DNA can be input to high-throughput DNA detection methods such as high-resolution DNA microarrays (MeDIP-chip) or next-generation sequencing (MeDIP-seq). Nonetheless, understanding of the methylome remains rudimentary; its study is complicated by the fact that, like other epigenetic properties, patterns vary from cell-type to cell-type.

<span class="mw-page-title-main">5-Hydroxymethylcytosine</span> Chemical compound

5-Hydroxymethylcytosine (5hmC) is a DNA pyrimidine nitrogen base derived from cytosine. It is potentially important in epigenetics, because the hydroxymethyl group on the cytosine can possibly switch a gene on and off. It was first seen in bacteriophages in 1952. However, in 2009 it was found to be abundant in human and mouse brains, as well as in embryonic stem cells. In mammals, it can be generated by oxidation of 5-methylcytosine, a reaction mediated by TET enzymes. Its molecular formula is C5H7N3O2.

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.

Epigenetics in insects is the role that epigenetics plays in insects.

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.

<span class="mw-page-title-main">5-Formylcytosine</span> Chemical compound

5-Formylcytosine (5fC) is a pyrimidine nitrogen base derived from cytosine. In the context of nucleic acid chemistry and biology, it is regarded as an epigenetic marker. Discovered in 2011 in mammalian embryonic stem cells by Thomas Carell's research group the modified nucleoside was more recently confirmed to be relevant both as an intermediate in the active demethylation pathway and as a standalone epigenetic marker. In mammals, 5fC is formed by oxidation of 5-Hydroxymethylcytosine (5hmC) a reaction mediated by TET enzymes. Its molecular formula is C5H5N3O2.

References

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Literature

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