Genomic size: 133942bp; Coding sequence: 6009 nt - 11 exons, 9 coding exons on plus strand.

From centromere to telomere.
Pre-mRNA alternative splicing produces at least 3 isoforms.

Name: 2-oxoglutarate tet methylcytosine dioxygenase 2.

The canonical isoform 1 is composed of 2002 amino acids.
The catalytic dioxygenase domain is located at the C-terminal part of the protein, inside a cysteine-rich region. Isoforms 2 and 3 appear as truncated proteins whose function is not yet well understood.

Wide, mainly in haematopoietic tissues and in some specialized areas of the nervous tissue.

Nuclear.

Methylcytosine dioxygenase dependant of α-ketoglutarate (α-KG, also called 2-oxoglutarate) and Fe⁺⁺, which catalyses conversion from 5-methylcytosine (5mC) to 5-dihydroxymethylcytosine (5hmC). TET proteins play a key role in epigenetic regulation of the transcription. The transition from 5mC to 5hmC, and later to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), is considered as a key step in the process of DNA demethylation at CpG islands and other sites. The enrichment in 5hmC in CpG islands near or inside promoter sites, as well as in intragenic regions, leads to increased gene expression. 5mC can be restored enzymatically from 5fC and 5caC, but not from 5hmC. The global epigenetic regulation of transcription seems to depend on the dynamic balance between 5mC and 5hmC (Branco et al., 2012; Kohli and Zhang, 2013) (figure 1).
The role of TET2 in haematopoiesis is pleiotropic, including self renewal of haematopoietic stem cells (HSCs), lineage commitment and cell line differentiation. TET2 is strongly expressed in progenitors and HSCs, and progressively repressed during differentiation. In mice the consequence of targeted inactivation of the Tet2 gene is a decrease of 5hmC and an increase of the number of mutated HSCs/progenitor cells, with a selective advantage over wt HSCs (Ko et al., 2011).
TET2 and TET3 proteins have a strong interaction with O-GlcNac transferase (OGT), independent from their catalytic activity on 5mC. OGT mediates the addition of O-GlcNac to ser and thr residues of many intracellular proteins. The link TET2/3-OGT promotes the activity of OGT: this complex binds to chromatin and contributes to promoters activation by enrichment in histone H3K4me3 (Solary et al., 2014).
Tet1 and Tet2 are also expressed in murine embryonic stem cells. To be noted the role of murine Tet2, in conjunction with the enzyme poly(ADP-ribose) polymerase-1 (Parp1), at an early stage of epigenetic reprogrammation of somatic cells into induced pluripotent stem cells (IPSCs) (Doege et al., 2012).

TET2 is one member of a family comprising the 3 evolutionary conserved genes TET1, TET2 and TET3 in mammals. Only TET1 and TET2 are involved in malignant haematological diseases. The 3 proteins have two highly conserved domains in the middle of the protein and at the C-terminal extremity. TET1 and TET3 contain also a CXXC DNA binding zinc finger domain at the N-terminal extremity, which is not present in TET2. However there is a CXXC domain in a gene named CXXC4 or IDAX located 650kb proximal from TET2, which results from a chromosomal inversion affecting the ancestral TET2 gene. IDAX is oriented and transcribed in opposite direction from TET2, it regulates its expression and would be involved in its DNA binding (Ko et al., 2013).

All types of somatic TET2 mutations were observed in cancer. The more prominent implication was described in haematological malignancies. However TET2 activity alteration, either by mutation or transcriptional mRNA reduction, was subsequently reported in a great variety of human tumours.
The implication of the gene in haematological malignancies was first detected after the observation of reciprocal translocations involving a sub microscopic 4q24 deletion in tumour cells (Viguié et al., 2005). All mutations alter the catalytic activity, leading to a loss-of-function of the enzyme. Nonsense and frame shift mutations, which result in a truncated protein, occur all over the gene. But critical missense mutations occur only in the two evolutionary conserved domains of TET2. Missense variations outside of these two domains are considered as germinal polymorphisms. Both copies of the gene are altered in less than half of the patients, suggesting a role for haploinsufficiency. Consequently TET2 must be considered as a tumour suppressor gene.
In murine models, the consequence of Tet2 inactivation is a depletion of 5hmC in bone marrow cells, an increase of the pool of HSCs, and an orientation of maturation towards monocyte/macrophage differentiation (Quivoron et al., 2011). The same effect is obtained in vitro on human cell lines or CD34+ cells, by shRNA knockdown of TET2 gene (Pronier et al., 2011).
Mutations of TET2 and of IDH1/IDH2 are mutually exclusive, suggesting that they act in the same pathway. IDH1 and IDH2 are the two genes coding for an isocitrate deshydrogenase, they catalyse the decarboxylation of isocitrate to α-ketoglutarate (α-KG) in the Krebs cycle. IDH mutations lead to a gain of function and the production of the R enantiomer of 2-hydroxyglutarate (R-2HG) instead of α-KG. As α-KG is a crucial cofactor for the activity of TET2, the protein is inactivated by the production of R-2HG instead of α-KG.
Mutations of IDH1/IDH2 are observed in many tumours including haematological malignancies with the same final epigenetic effect as TET2 inactivation, mainly a global promoter hypermethylation.