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Tet methylcytosine dioxygenase 2 (''TET2'') is a human
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. It resides at
chromosome 4 Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs (the building material of DNA) and represents between 6 and 6.5 percent of the t ...
q24, in a region showing recurrent microdeletions and copy-neutral loss of
heterozygosity Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
(CN-LOH) in patients with diverse myeloid malignancies.


Function

''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. In these two papers, Kriaucionis and Heintz provided evidence that a high abundance of 5hmC can be found in specific tissues and Tahiliani et al. 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), a positive global regulator of gene transcription that is named after its role cancer regulation. An explanation for protein function was provided in 2009 via computational search for
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s 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 ''Trypanosoma brucei'' is a species of parasitic Kinetoplastida, kinetoplastid belonging to the genus ''Trypanosoma'' that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclus ...
'' 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, although the evidence of an unusual form of DNA modification goes back to at least the mid 1980s. In two articles published back-to-back in ''
Science Science is a systematic endeavor that builds and organizes knowledge in the form of testable explanations and predictions about the universe. Science may be as old as the human species, and some of the earliest archeological evidence for ...
'' journal in 2011, firstly it was demonstrated that (1) TET converts 5mC to 5fC and 5caC, and (2) 5fC and 5caC are both present in mouse
embryonic stem cell Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consi ...
s and organs, and secondly 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 cell Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage pre- implantation embryo. Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consi ...
s. 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). The “
thymine Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nu ...
” 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 Thymine () ( symbol T or Thy) is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The others are adenine, guanine, and cytosine. Thymine is also known as 5-methyluracil, a pyrimidine nu ...
. Only in 2011, two publications demonstrated the activity for TDG as also excising the oxidation products of 5-methylcytosine. Furthermore, in the same year 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 by evidence of base excision repair coupled with TET and TDG. In simple terms, TET–TDG–BER produces
demethylation 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 at ...
; TET proteins oxidise 5mC to create the substrate for TDG-dependent excision.
Base excision repair 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 t ...
then replaces 5mC with C.


Clinical significance

The most striking outcome of aberrant TET activity is its association with the development of cancer. Mutations in this
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
were first identified in myeloid
neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s with deletion or uniparental disomy at 4q24. TET2 may also be a candidate for active
DNA demethylation For molecular biology in mammals, DNA demethylation causes replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C) (see figure of 5mC and C). DNA demethylation can occur by an active process at the site of a 5mC in a DNA sequenc ...
, 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. 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 5 In mice the depletion of TET2 skewed the differentiation of
haematopoietic Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...
precursors, as well as amplifying the rate of haematopoietic or progenitor cell renewal.
Somatic Somatic may refer to: * Somatic (biology), referring to the cells of the body in contrast to the germ line cells ** Somatic cell, a non-gametic cell in a multicellular organism * Somatic nervous system, the portion of the vertebrate nervous sys ...
TET2 mutations are frequently observed in
myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...
s (MDS),
myeloproliferative neoplasms Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. ''Myelo'' refers to the bone marrow, ''proliferative'' describes the rapid growt ...
(MPN), MDS/MPN overlap syndromes including
chronic myelomonocytic leukaemia Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are in ...
(CMML),
acute myeloid leukaemia 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 ...
s (AML) and secondary AML (sAML). ''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. 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. Loss-of-function due to somatic variants are frequently reported in cancer, however
homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
germline 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 ...
loss-of-function has been shown in humans, causing childhood
immunodeficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
and
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
. The phenotype of
immunodeficiency Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
, autoimmunity and lymphoproliferation highlights requisite roles of TET2 in the
human immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, ...
.


WIT pathway

''TET2'' is mutated in 7%–23% of acute myeloid leukemia (AML) patients. Importantly, ''TET2'' is mutated in a
mutually exclusive In logic and probability theory, two events (or propositions) are mutually exclusive or disjoint if they cannot both occur at the same time. A clear example is the set of outcomes of a single coin toss, which can result in either heads or tails ...
manner with ''
WT1 Wilms tumor protein (WT33) is a protein that in humans is encoded by the ''WT1'' gene on chromosome 11p. Function This gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-ric ...
'', ''
IDH1 Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the ''IDH1'' gene on chromosome 2. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two ...
'', and ''
IDH2 Isocitrate dehydrogenase ADP mitochondrial is an enzyme that in humans is encoded by the ''IDH2'' gene. Isocitrate dehydrogenases are enzymes that catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to tw ...
''. TET2 can be recruited by WT1, a sequence-specific zinc finger
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
, to WT1-target genes, which it then activates by converting methylcytosine into 5-hydroxymethylcytosine at the genes’ promoters. 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. Together, ''WT1'', ''IDH1/2'' and ''TET2'' define the WIT pathway in AML. 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.


References


Further reading

* * * {{Use dmy dates, date=April 2017 Genes on human chromosome 4