Review Article
TET Genes: new players in DNA demethylation and important determinants for stemness

https://doi.org/10.1016/j.exphem.2010.12.004Get rights and content

Stem cells are defined as cells that have the ability to perpetuate themselves through self-renewal and to generate functional mature cells by differentiation. During each stage, coordinated gene expression is crucial to maintain the balance between self-renewal and differentiation. Disturbance of this accurately balanced system can lead to a variety of malignant disorders. In mammals, DNA cytosine-5 methylation is a well-studied epigenetic pathway that is catalyzed by DNA methyltransferases and is implicated in the control of balanced gene expression, but also in hematological malignancies. In this review, we focus on the TET (ten-eleven-translocation) genes, which recently were identified to catalyze the conversion of cytosine-5 methylation to 5-hydroxymethyl-cytosine, an intermediate form potentially involved in demethylation. In addition, members of the TET family are playing a role in ES cell maintenance and inner cell mass cell specification and were demonstrated to be involved in hematological malignancies. Recently, a correlation between low genomic 5-hydroxymethyl-cytosine and TET2 mutation status was shown in patients with myeloid malignancies.

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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)

  • O. Kosmider et al.

    TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs)

    Blood

    (2009)
  • R. Holliday et al.

    DNA modification mechanisms and gene activity during development

    Science

    (1975)
  • W. Reik et al.

    Epigenetic reprogramming in mammalian development

    Science

    (2001)
  • A.D. Riggs

    X inactivation, differentiation, and DNA methylation

    Cytogenet Cell Genet

    (1975)
  • R. Jaenisch et al.

    Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals

    Nat Genet

    (2003)
  • R. Lister et al.

    Human DNA methylomes at base resolution show widespread epigenomic differences

    Nature

    (2009)
  • L.J. Cliffe et al.

    JBP1 and JBP2 are two distinct thymidine hydroxylases involved in J biosynthesis in genomic DNA of African trypanosomes

    Nucleic Acids Res

    (2009)
  • Z. Yu et al.

    The protein that binds to DNA base J in trypanosomatids has features of a thymidine hydroxylase

    Nucleic Acids Res

    (2007)
  • S. Kriaucionis et al.

    The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain

    Science

    (2009)
  • M. Tahiliani et al.

    Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1

    Science

    (2009)
  • J.C. Chuang et al.

    Epigenetics and microRNAs

    Pediatr Res

    (2007)
  • E. Jost et al.

    EHA scientific workshop report: the role of epigenetics in hematological malignancies

    Epigenetics

    (2007)
  • R.B. Lorsbach et al.

    TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23)

    Leukemia

    (2003)
  • R. Ono et al.

    LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23)

    Cancer Res

    (2002)
  • S. Ito et al.

    Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification

    Nature

    (2010)
  • K. Hussein et al.

    Cytogenetic correlates of TET2 mutations in 199 patients with myeloproliferative neoplasms

    Am J Hematol

    (2010)
  • R.L. Strausberg et al.

    Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences

    Proc Natl Acad Sci U S A

    (2002)
  • S.M.C. Langemeijer et al.

    Acquired mutations in TET2 are common in myelodysplastic syndromes

    Nat Genet

    (2009)
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