5-Hydroxymethylcytosine
Encyclopedia
5-Hydroxymethylcytosine is a DNA
pyrimidine
nitrogen base. It is formed from the DNA base cytosine
by adding a methyl group and then a hydroxy group. It is 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 the Tet family of enzymes. Its molecular formula is C5H7N3O2.
. The amount of hydroxymethylcytosine increases with age, as shown in mouse hippocampus
and cerebellum
.
expression or prompt DNA demethylation
. This hypothesis is supported by the fact that artificial DNA that contains 5-hydroxymethylcytosines can be converted into unmodified cytosines once introduced into mammalian cells. Additionally, 5-Formylcytosine, an oxidation product of 5-Hydroxymethylcytosine and possible intermediate of an oxidative demethylation pathway was detected in DNA from embryonic stem cells. Interestingly, no significant amounts of putative demethylation intermediates could be detected in mouse tissue. 5-Hydroxymethylcytosine may be especially important in the central nervous system
, as it is found in very high levels there.
in two different neurons. He discovered a significant amount of an unknown substance instead, and after conducting several tests, discovered that the substance was 5-hydroxymethylcytosine.
The lab of L. Aravind used bioinformatic tools to predict that the Tet family of enzymes would likely oxidize 5-methylcytosine to 5-hydroxymethylcytosine. This was demonstrated in vitro
and in live human and mouse cells by scientists working in the labs of Anjana Rao and David Liu.
5-Hydroxymethylcytosine was originally observed in mammals in 1972 by R. Yura, but this initial finding is dubious. Yura found 5-hmC present at extremely high levels in rat brain and liver, completely supplanting 5-methylcytosine. This contradicts all research conducted on mammalian DNA composition conducted before and since, including the Heintz and Rao papers, and another group was unable to reproduce Yura's result.
With the discovery of 5-hydroxymethylcytosine some concerns have been raised regarding DNA methylation studies using the bisulfite sequencing technique. 5-hydroxymethylcytosine has been shown to behave like its precursor, 5-methylcytosine, in bisulfite conversion experiments. Therefore, bisulfite sequencing data may need to be revisited to verify whether the detected modified base is 5-methylcytosine or 5-hydroxymethylcytosine.
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
pyrimidine
Pyrimidine
Pyrimidine is a heterocyclic aromatic organic compound similar to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-member ring...
nitrogen base. It is formed from the DNA base cytosine
Cytosine
Cytosine is one of the four main bases 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...
by adding a methyl group and then a hydroxy group. It is important in epigenetics
Epigenetics
In biology, and specifically genetics, epigenetics is the study of heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence – hence the name epi- -genetics...
, 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
Human
Humans are the only living species in the Homo genus...
and mouse
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
brains, as well as in embryonic stem cells. In mammals, it can be generated by oxidation of 5-methylcytosine
5-Methylcytosine
5-Methylcytosine is a methylated form of the DNA base cytosine that may be involved in the regulation of gene transcription. When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered .In the figure on the right, a methyl group, is...
, a reaction mediated by the Tet family of enzymes. Its molecular formula is C5H7N3O2.
Localization
Every mammalian cell seems to contain 5-Hydroxymethylcytosine, but the levels vary significantly depending on the cell type. The highest levels are found in neuronal cells of the central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. The amount of hydroxymethylcytosine increases with age, as shown in mouse hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
.
Function
The exact function of this nitrogen base is still not fully elucidated, but it is thought that it may regulate geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
expression or prompt DNA demethylation
DNA demethylation
DNA demethylation is a process of removal of methyl group from nucleotide in DNA. DNA demethylation could be passive and active. Passive process takes place in the absence of methylation of newly synthesised DNA strands by DNMT1 during several replication rounds...
. This hypothesis is supported by the fact that artificial DNA that contains 5-hydroxymethylcytosines can be converted into unmodified cytosines once introduced into mammalian cells. Additionally, 5-Formylcytosine, an oxidation product of 5-Hydroxymethylcytosine and possible intermediate of an oxidative demethylation pathway was detected in DNA from embryonic stem cells. Interestingly, no significant amounts of putative demethylation intermediates could be detected in mouse tissue. 5-Hydroxymethylcytosine may be especially important in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, as it is found in very high levels there.
History
5-Hydroxymethylcytosine was observed by Skirmantas Kriaucionis, an associate at the Heintz lab, who was looking for levels of 5-methylcytosine5-Methylcytosine
5-Methylcytosine is a methylated form of the DNA base cytosine that may be involved in the regulation of gene transcription. When cytosine is methylated, the DNA maintains the same sequence, but the expression of methylated genes can be altered .In the figure on the right, a methyl group, is...
in two different neurons. He discovered a significant amount of an unknown substance instead, and after conducting several tests, discovered that the substance was 5-hydroxymethylcytosine.
The lab of L. Aravind used bioinformatic tools to predict that the Tet family of enzymes would likely oxidize 5-methylcytosine to 5-hydroxymethylcytosine. This was demonstrated in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
and in live human and mouse cells by scientists working in the labs of Anjana Rao and David Liu.
5-Hydroxymethylcytosine was originally observed in mammals in 1972 by R. Yura, but this initial finding is dubious. Yura found 5-hmC present at extremely high levels in rat brain and liver, completely supplanting 5-methylcytosine. This contradicts all research conducted on mammalian DNA composition conducted before and since, including the Heintz and Rao papers, and another group was unable to reproduce Yura's result.
With the discovery of 5-hydroxymethylcytosine some concerns have been raised regarding DNA methylation studies using the bisulfite sequencing technique. 5-hydroxymethylcytosine has been shown to behave like its precursor, 5-methylcytosine, in bisulfite conversion experiments. Therefore, bisulfite sequencing data may need to be revisited to verify whether the detected modified base is 5-methylcytosine or 5-hydroxymethylcytosine.
External links
See also
- hydroxylationHydroxylationHydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
- methylationMethylationIn the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
- nitrogen base