| TET2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
 | |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | TET2 , KIAA1546, MDS, tet methylcytosine dioxygenase 2, Tet methylcytosine dioxygenase 2, IMD75 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 612839 MGI: 2443298 HomoloGene: 49498 GeneCards: TET2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Tet methylcytosine dioxygenase 2 (TET2) is a human gene. [5] 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.
TET2 encodes a protein that catalyzes the conversion of the modified DNA base methylcytosine to 5-hydroxymethylcytosine.
The first mechanistic reports showed tissue-specific accumulation of 5-hydroxymethylcytosine (5hmC) and the conversion of 5mC to 5hmC by TET1 in humans in 2009. [6] [7] In these two papers, Kriaucionis and Heintz [6] provided evidence that a high abundance of 5hmC can be found in specific tissues and Tahiliani et al. [7] demonstrated the TET1-dependent conversion of 5mC to 5hmC. A role for TET1 in cancer was reported in 2003 showing that it acted as a complex with MLL (myeloid/lymphoid or mixed-lineage leukaemia 1) (KMT2A), [8] [9] a positive global regulator of gene transcription that is named after its role cancer regulation. An explanation for protein function was provided in 2009 [10] via computational search for enzymes that could modify 5mC. At this time, methylation was known to be crucial for gene silencing, mammalian development, and retrotransposon silencing. The mammalian TET proteins were found to be orthologues of Trypanosoma brucei base J-binding protein 1 (JBP1) and JBP2. Base J was the first hypermodified base that was known in eukaryotic DNA and had been found in T. brucei DNA in the early 1990s, [11] although the evidence of an unusual form of DNA modification goes back to at least the mid 1980s. [12]
In two articles published back-to-back in Science journal in 2011, firstly [13] it was demonstrated that (1) TET converts 5mC to 5fC and 5caC, and (2) 5fC and 5caC are both present in mouse embryonic stem cells and organs, and secondly [14] that (1) TET converts 5mC and 5hmC to 5caC, (2) the 5caC can then be excised by thymine DNA glycosylase (TDG), and (3) depleting TDG causes 5caC accumulation in mouse embryonic stem cells.
In general terms, DNA methylation causes specific sequences to become inaccessible for gene expression. The process of demethylation is initiated through modification of the 5mC to 5hmC, 5fC, etc. To return to the unmodified form of cytosine (C), the site is targeted for TDG-dependent base excision repair (TET–TDG–BER). [13] [15] [16] The “thymine” in TDG (thymine DNA glycosylase) might be considered a misnomer; TDG was previously known for removing thymine moieties from G/T mismatches.
The process involves hydrolysing the carbon-nitrogen bond between the sugar-phosphate DNA backbone and the mismatched thymine. Only in 2011, two publications [13] [14] demonstrated the activity for TDG as also excising the oxidation products of 5-methylcytosine. Furthermore, in the same year [15] it was shown that TDG excises both 5fC and 5caC. The site left behind remains abasic until it is repaired by the base excision repair system. The biochemical process was further described in 2016 [16] by evidence of base excision repair coupled with TET and TDG.
In simple terms, TET–TDG–BER produces demethylation; TET proteins oxidise 5mC to create the substrate for TDG-dependent excision. Base excision repair then replaces 5mC with C.
The most striking outcome of aberrant TET activity is its association with the development of cancer.
Mutations in this gene were first identified in myeloid neoplasms with deletion or uniparental disomy at 4q24. [17] TET2 may also be a candidate for active DNA demethylation, the catalytic removal of the methyl group added to the fifth carbon on the cytosine base.
Damaging variants in TET2 were attributed as the cause of several myeloid malignancies around the same time as the protein’s function was reported for TET-dependent oxidation. [18] [19] [20] [21] [22] [23] [24] Not only were damaging TET2 mutations found in disease, but the levels of 5hmC were also affected, linking the molecular mechanism of impaired demethylation with disease [75]. [25] In mice the depletion of TET2 skewed the differentiation of haematopoietic precursors, [25] as well as amplifying the rate of haematopoietic or progenitor cell renewal. [26] [27] [28] [29]
Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). [30]
TET2 mutations have prognostic value in cytogenetically normal acute myeloid leukemia (CN-AML). "Nonsense" and "frameshift" mutations in this gene are associated with poor outcome on standard therapies in this otherwise favorable-risk patient subset. [31]
Loss-of-function TET2 mutations may also have a possible causal role in atherogenesis as reported by Jaiswal S. et al, as a consequence of clonal hematopoiesis. [32] Loss-of-function due to somatic variants are frequently reported in cancer, however homozygous germline loss-of-function has been shown in humans, causing childhood immunodeficiency and lymphoma. [33] The phenotype of immunodeficiency, autoimmunity and lymphoproliferation highlights requisite roles of TET2 in the human immune system.
TET2 is mutated in 7%–23% of acute myeloid leukemia (AML) patients. [34] Importantly, TET2 is mutated in a mutually exclusive manner with WT1 , IDH1 , and IDH2 . [35] [36] TET2 can be recruited by WT1, a sequence-specific zinc finger transcription factor, to WT1-target genes, which it then activates by converting methylcytosine into 5-hydroxymethylcytosine at the genes’ promoters. [36] Additionally, isocitrate dehydrogenases 1 and 2, encoded by IDH1 and IDH2, respectively, can inhibit the activity of TET proteins when present in mutant forms that produce the TET inhibitor D-2-hydroxyglutarate. [37] Together, WT1, IDH1/2 and TET2 define the WIT pathway in AML. [34] [36] The WIT pathway might also be more broadly involved in suppressing tumor formation, as a number of non-hematopoietic malignancies appear to harbor mutations of WIT genes in a non-exclusive manner. [34]
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.
Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen atoms.
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.
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.
Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. Occasionally, spread may occur to the brain, skin, or gums. As an acute leukemia, AML progresses rapidly, and is typically fatal within weeks or months if left untreated.
Acute monocytic leukemia is a type of acute myeloid leukemia. In AML-M5 >80% of the leukemic cells are of monocytic lineage. This cancer is characterized by a dominance of monocytes in the bone marrow. There is an overproduction of monocytes that the body does not need in the periphery. These overproduced monocytes interfere with normal immune cell production which causes many health complications for the affected individual.
Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).
Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the RUNX1 gene.
MN1 is a gene found on human chromosome 22, with gene map locus 22q12.3-qter. Its official full name is meningioma 1 because it is disrupted by a balanced translocation (4;22) in a meningioma.
Wilms tumor protein (WT33) is a protein that in humans is encoded by the WT1 gene on chromosome 11p.
Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.
G/T mismatch-specific thymine DNA glycosylase is an enzyme that in humans is encoded by the TDG gene. Several bacterial proteins have strong sequence homology with this protein.
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.
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 3 is a protein that in humans is encoded by the TET3 gene.
Anjana Rao is a cellular and molecular biologist of Indian ethnicity, working in the US. She uses immune cells as well as other types of cells to understand intracellular signaling and gene expression. Her research focuses on how signaling pathways control gene expression.
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.
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.
Beck–Fahrner syndrome, also known as BEFAHRS and TET3 deficiency, is a rare genetic disorder caused by mutations of the TET3 gene. It can occur de novo or can be inherited in an autosomal dominant manner. Mutations in the TET3 gene disrupts DNA demethylation during early embryogenesis and neural development. Most common clinical presentation includes global developmental delay, psychomotor retardation, neurodevelopmental disorders, hypotonia, epilepsy and dysmorphic features. It is diagnosed using molecular and genetic testing in setting of typical symptoms. Management is supportive and intended to improve quality of life.
