| TET3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | TET3 , hCG_40738, tet methylcytosine dioxygenase 3, BEFAHRS | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 613555 MGI: 2446229 HomoloGene: 35360 GeneCards: TET3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Tet methylcytosine dioxygenase 3 is a protein that in humans is encoded by the TET3 gene. [5]
Tet3 and its respective protein TET 3 are members of the TET (ten-eleven-translocation) family of genes and proteins that play a role in DNA demethylation. [6] DNA demethylation is the removal of suppressive methyl groups from the cytosine of DNA. [6] Demethylating the DNA and removing these markers is associated with increased transcription. [6] Since DNA methylation is a relatively strong and stable marker it is not often removed. However, there are important points in an organism’s life when these marks benefit from being removed so that certain genes can be accessed and transcribed.
One of which is right after an egg and sperm have come together to form a zygote. The methylation marks from the parent cells must be removed so that certain genes can be accessed and transcribed for the zygote to mature into a fully grown organism. [6] Tet3 plays an important role here. The TET3 protein works to demethylate the genome of the fertilized zygote to allow it to grow into a fully developed organism. It does this by starting a series of oxidation reactions that convert the methylated cytosine on the DNA from 5-methyl cytosine (5mC) into 5-hydroxymethylcytosine (5hmC). [6] This cytosine base then goes through a further series of reactions after which it can be removed either passively through replication-dependent dilution or actively by the enzyme thymidine DNA glycosylase and replaced with an unmethylated cytosine base. [6] Once this occurs the DNA is now more accessible for transcription.
There are certain tissues that rely heavily on Tet3 for their development. For example, TET3 is found in large quantities in neurons and is important for their development and maturation. [7] While there is not much work regarding the role of Tet3 in humans, studies have been done on model organisms such as mice, frogs, and rats. An experiment done by several researchers on mice showed that Tet3 is most active in NPC or Neuronal Progenitor Cells. [7] These cells are the progenitors of mature neurons and begin to develop shortly after a zygote is formed. Once an embryonic stem cell begins to differentiate into an NPC, Tet3 becomes upregulated. [7] The researchers speculate that this occurs in order to demethylate genes associated with neuronal maturation so they can be transcribed. [7] While Tet3 is not important for the commitment of an embryonic stem cell to turn into an NPC, it is important for maintaining the cell as an NPC and eventually turning it into a mature neuron. The complete absence or knockout of Tet3 in mouse cells leads to increased apoptosis of neurons, demonstrating how important the gene is to neuronal development. [7]
In addition, Tet3 is important for repair and upkeep in mature neurons. Epigenetic markers, especially ones that make the DNA more accessible, are important after cell damage because they can turn on genes that function in cell repair. [8] A recent study done in vivo in rats has shown that the TET3 protein is important in recovery after a stroke. The study shows that TET3 as well as its product, 5-hydroxymethylcytosine (5hmC), are expressed more after focal ischemia in order to demethylate and turn on genes associated with DNA repair in neurons. [8] Knockdown of the TET3 protein in these rats led to increased neuron damage after a stroke and a decreased expression of several genes that aid in neuron repair. [8] These results not only demonstrate the importance of Tet3 in neuronal repair but also suggest Tet3 and its protein as a possible therapeutic target for future studies that could aid patients in neuronal repair after a stroke.
In humans, less is known about the exact role of Tet3 in neurons. Current studies in humans are focusing on the effects of mutant Tet3 on an individual’s phenotype. While the complete knockout of Tet3 appears to be fatal to the developing zygote, the mutation of one or more alleles of Tet3 can result in viable offspring. [9] These mutations of Tet3 can greatly affect the TET3 protein and lead to a class of neurodevelopmental disorders in humans known as Beck–Fahrner syndrome. [9] Individuals with these mutations experience phenotypes such as developmental delay and growth abnormalities as well as features found in other neurodevelopmental disorders such as Sotos Syndrome and Autism Spectrum Disorder. [9]
Little is known about the exact mutations on Tet3 that cause Beck–Fahrner syndrome and their inheritance patterns. However, the mutations seem to follow a Mendelian pattern of inheritance. [9] In a recent study of affected individuals and their families, some were found to have autosomal-dominant patterns of inheritance while others were found to have autosomal-recessive patterns of inheritance. [9] Regardless of the inheritance pattern, all mutations in this gene were shown to be caused by either a missense variant in the region of the gene that codes for the catalytic domain of TET3 or a frameshift or nonsense variant in the same region. [9] The region in which this mutation occurs is highly conserved among species, especially mice and humans, which is why work done on model organisms may be useful in bettering our understanding of Tet3’s function in humans. [9]
In conclusion, the Tet3 gene is important in a variety of organisms including humans, rats, and mice. It functions mostly during the formation of a zygote, particularly in neurons. There it helps neurons mature and develop as well as aids them in repair.
Mutations in this gene can result in Beck–Fahrner syndrome, which has been associated a number of abnormal phenotypic features including intellectual disability, developmental delay, hypotonia, autistic traits, movement disorders, growth abnormalities and facial dysmorphism. [9]
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.
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.
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.
A regulatory sequence is a segment of a nucleic acid molecule which is capable of increasing or decreasing the expression of specific genes within an organism. Regulation of gene expression is an essential feature of all living organisms and viruses.
In biology and genetics, the germline is the population of a multicellular organism's cells that pass on their genetic material to the progeny (offspring). In other words, they are the cells that form the egg, sperm and the fertilised egg. They are usually differentiated to perform this function and segregated in a specific place away from other bodily cells.
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.
Immediate early genes (IEGs) are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized. IEGs are distinct from "late response" genes, which can only be activated later, following the synthesis of early response gene products. Thus IEGs have been called the "gateway to the genomic response". The term can describe viral regulatory proteins that are synthesized following viral infection of a host cell, or cellular proteins that are made immediately following stimulation of a resting cell by extracellular signals.
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.
DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.
Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch or long-patch BER.
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.
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.
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.
8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.
Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) is a member of the TET family of enzymes, in humans it is encoded by the TET1 gene. Its function, regulation, and utilizable pathways remain a matter of current research while it seems to be involved in DNA demethylation and therefore gene regulation.
Tet methylcytosine dioxygenase 2 (TET2) is a human gene. It resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies.
Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). In short, it is brain growth in relation to its organization. This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells (NECs), radial glial cells (RGCs), basal progenitors (BPs), intermediate neuronal precursors (INPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others.
AlkB homolog 1, histone H2A dioxygenase is a protein that in humans is encoded by the ALKBH1 gene.
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.
Beck–Fahrner syndrome, also known as BEFAHRS and TET3 deficiency, is a rare genetic disorder caused by mutations of the TET3 gene. The clinical presentation varies among individuals, but typically includes global developmental delay, slow progress in mental and physical activities, autism, decreased muscle tone, epilepsy and dysmorphic features.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
