Review ArticleTET Genes: new players in DNA demethylation and important determinants for stemness
Section snippets
Gene and protein structure of TET members
The TET family consists of three members, namely TET1, TET2, and TET3. TET1 is located on 10q21 and contains 12 exons spanning a sequence of 134 kb. The mRNA has a length of 9.6 kb, while the coding sequence consists of about 6.4 kb coding for a protein of 2136 amino acids (AA) [18]. TET2 is located on 4q24 and spans 96 kb coding for an mRNA with the size of 9.7 kb and a coding sequence of 6 kb, although translation results in a protein of 2002 AA [19]. The TET2 gene contains 11 exons [20], and
Role of TET proteins in DNA modification
In early embryogenesis, CpG methylation is essential for X-inactivation and asymmetric expression of imprinted genes [26]. Methylation of CpG islands in somatic cells shows a general correlation with gene expression. CpG-DNA modifications other than methylation are primarily known from caudate bacteriophages, which modify bases such as 5-hydroxymethylpyrimidines and their mono- or diglycosylated derivatives, and N6-carbamoylmethyl adenines to counter host DNA restriction responses [27]. Another
TET genes as potentially key players in embryonic stem cells maintenance
Recently, the expression of Tet1 and Tet2 was shown in murine ES cells (E14). Interestingly, Tet3, which is highly expressed in most of the organs including human hematopoietic stem cells and murine V6.5 ES cells, is not expressed in murine E14 ES cells 10, 17. The Zhang group could demonstrate with their findings that knockdown of Tet1 in ES cells via shRNA results in morphological abnormalities and a decrease of alkaline phosphatase activity. Furthermore, a reduced cell growth was observed,
TET genes in normal hematopoiesis
All three TET genes showed broad expression pattern in different tissues, they are abundantly expressed in most of the normal hematopoietic cells. In contrast to TET1, TET2 and TET3 are higher expressed in hematopoietic cells 21, 31. Among the hematopoietic subpopulations expression of TET2 and TET3 are highest in granulocytes. Induction of granulocytic differentiation in the promyelocytic cell line NB4 showed upregulation of TET2 expression [21]. Furthermore, all aforementioned TET2 isoforms
TET1 in AML and acute lymphoblastic leukemia
In 2002, the TET1 gene, previously called LCX (leukemia-associated protein with a CXXC domain), had been identified as a fusion partner of the mixed lineage leukemia (MLL) gene in an adult AML patient with translocation t(10;11)(q22;q23). Later, a t(10;11) translocation was also found in a pediatric AML patients and patients with acute lymphoblastic leukemia 14, 15, 16. Translocations, which create fusion genes with MLL, are associated with truncation of MLL and often predict a poor prognosis
TET2 mutation status and clinical outcome in myeloid disorders
The direct influence of mutations in TET2 on patient survival in myeloid disorders currently remains a contentious issue. In the study performed by Abdel-Wahab et al., patients suffering from AML seemed to have a decreased survival rate when associated with a mutant form of TET2 compared to WT group (p = 0.0294) [18], while in the study from Nibourel et al. no significant impact on clinical outcome was seen [49], but mutated TET2 was strongly associated with mutated NPM1. In a recent study
Catalytic activity of Tet2 is compromised by mutations in predicted catalytic residues
As TET genes have been shown to catalyze the conversion of 5mC to 5hmC, it would be interesting to test whether TET2 mutations found in patients impair its enzymatic activity. In a very elegant study recently conducted by Ko et al. [32], patients with myeloid malignancies were analyzed with respect to the amount of genomic 5hmC and TET2 mutations. By using dotblot quantification assay, the group could find a correlation between low genomic 5hmC and TET2 mutation status. Remarkably, TET2
TET3 mutations are not (yet) reported in malignancies
TET3 seems to be the only gene of this family, which is not directly involved in hematologic malignancies. There is only one case documented of a patient with RARS and idiopathic myelofibrosis, that showed a deletion in 2p23 including TET3 [47]. However, whether the deletion of TET3 contributed to the malignant transformation in this patient remained unclear.
Future perspectives of TET-mediated demethylation
DNA demethylation is not only important for overcoming gene silencing, but is also central to reprogram somatic nuclei to a pluripotent stage, an important step in the production of iPS. Extensive efforts in identifying demethylating enzymes had not yielded favorable results until recently when activation induced cytidine deaminase (AID) and an elongator complex protein were identified [56]. In this study, Bhutani et al. [56] have shown that AID binds and demethylates promoters of the two key
Conflict of interest disclosure
No financial interest/relationships with financial interest relating to the topic of this article have been declared.
References (56)
- et al.
DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development
Cell
(1999) - et al.
DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia
Cancer Cell
(2010) - et al.
The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group
Blood
(2009) - et al.
Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies
Blood
(2009) - et al.
New TET2 gene mutations in patients with myeloproliferative neoplasms and splanchnic vein thrombosis
J Thromb Haemost
(2010) - et al.
Analysis of the ten-eleven translocation 2 (TET2) gene in familial myeloproliferative neoplasms
Blood
(2009) - et al.
Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms
Blood
(2010) - et al.
Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm
Blood
(2010) - et al.
Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms
Blood
(2009) - et al.
Next-generation sequencing of the TET2 gene in 355 MDS and CMML patients reveals low abundance mutant clones with early origins, but indicates no definite prognostic value
Blood
(2010)