Flora D'Anna
Maria Chiara De Santis
DEFINITION
Ten Eleven Translocation 2 (TET2) is a member of TET family, which includes TET1, TET2 and TET3 proteins. TET proteins display the typical features of 2-oxoglutarate (2OG) - and Fe(II)-dependent dioxygenases (2OGFeDO).
TET2 is involved in oxidative modifications of bases in nucleic acids, in particular it catalyzes the convertion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) (Advances in DNA methylation: 5-hydroxymethylcytosine revisited, 2011).
THE GENE
CHEMICAL STRUCTURE AND IMAGES
TET family is characterized by an amino-terminal CXXC-type zinc finger domain and a carboxy-terminal catalytic Fe(II)- and 2-oxoglutarate-dependent dioxygenase domain with an inserted cysteine-rich domain. In jawed vertebrates, TET genes underwent triplication and a subsequent chromosomal inversion split the TET2 gene into distinct segments, encoding the catalytic and CXXC domains. The ancestral CXXC domain of TET2 is now encoded by a distinct gene, IDAX, which is transcribed in the opposite direction. The IDAX protein (367 aa)
incorporates a 52-aa CXXC domain that is highly homologous to the CXXC domains of TET1 and TET3. Moreover, IDAX was firstly discovered as a regulator of Wnt signaling.
(Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX, 2013)
The catalytic dioxygenase domain shows eight antiparallel b-sheets constituting the Jelly-roll motif. This motif binds the cosubstrate 2OG and the cofactors Fe(II) and O2.
(A mechanistic overview of TET-mediated 5-methylcytosine oxidation, 2013)
Protein Aminoacids Percentage
Isoforms Comparison
SYNTHESIS AND TURNOVER
mRNA Expression
TET2 is expressed in multiple tissues on mRNA level, but expression is highest in hematopoietic cells, particularly granulocytes (TET proteins in malignant hematopoiesis, 2009).
(Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification, 2010)
mRNA Regulation
TET family mRNA is a direct target of microRNA miR-22 (The Oncogenic MicroRNA miR-22 Targets the TET2 Tumor Suppressor to Promote Hematopoietic Stem Cell Self-Renewal and Transformation, 2013; MicroRNA-Antagonism Regulates Breast Cancer Stemness and Metastasis via TET-Family-Dependent Chromatin Remodeling, 2013)
Protein Degradation
IDAX both recruits TET2 to target genes and regulates its protein stability. In particular, IDAX induces TET2 protein degradation by the activation of caspases (Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX, 2013).
Especially, it has been proposed a novel autoregulatory mechanism to maintain the hypomethylated state: IDAX can bind unmethylated DNA and recruit TET2 for 5mC conversion and at the same time trigger degradation of TET2 in a caspase-dependent fashion.
(The CXXC-TET bridge - mind the methylation gap!, 2013)
This novel property not only functions to dynamically maintain the unmethylated state, but also potentially explains the tissue-specific variation in hydroxymethylated DNA levels.
So, IDAX sets up additional possible links between well-characterized paracrine cell signaling networks (Wnt pathways) and DNA modification.
CELLULAR FUNCTIONS
TET2 is involved in several key processes such as positive regulation of transcription and cell differentiation. For this reason, its mutations are often involved in hemopoietic deseases.
Cellular Localization
TET2 is a nuclear protein. Its localization is regulated by Aid (Activation-induced cytidine deaminase) and IDAX proteins.
Aid has an effect on the subcellular localization of the Tet family and this is associated with Aid shuttling (Activation-Induced Cytidine Deaminase Alters the Subcellular Localization of Tet Family Proteins, 2012).
Mutations in IDAX CXXC domain impair TET2 nuclear localization (Modulation of TET2 expression and 5-methylcytosine oxidation by the CXXC domain protein IDAX,2013).
Molecular Function
(DNA methylation and methylcytosine oxidation in cell fate decisions, 2013)
TET family, which is a Fe(II) and 2-OG-dependent dioxygenase, utilizes molecular oxygen to transfer a hydroxyl group to 5mC in the catalytic conversion of 5mC to 5hmC. 2-OG is produced by isocitrate dehydrogenase (IDH). Moreover, TET family can oxidize 5hmC to 5-formylcytosine and 5-carboxylcytosine.
TET2 has a role in the manteinance of DNA demethylation; in fact, its oxydated products are deaminated by Aid in 5-hydroxy-uracil, which is replaced with unmodified cytosine by base excision repair system.
Activity Regulation
Oxidative stress enhances TET2 activity because it decreases NADPH and NADH levels, promoting TCA cycle reactions and so the IDH-dependent 2-OG production.
(Hypothesis Enviromental regulation of 5-hydroxymethyl-cytosine by oxidative stress, 2011)
In addition, it seems that ascorbate enhances 5hmC generation acting as a cofactor for Tet2.
(Ascorbate Induces Ten-Eleven Translocation (Tet) Methylcytosine Dioxygenase-mediated Generation of 5-Hydroxymethylcytosine, 2013)
INVOLVEMENT IN DISEASE
The first evidence suggesting that TET proteins could be involved in human cancer came with the identification of TET1 as a fusion partner in a rare translocation in leukemia. Specifically, TET1 was found to be fused with the myeloid/lymphoid or mixed-lineage leukemia gene (MLL) in acute myeloid leukemia (AML) patients, carrying a t(10;11)(q22;q23) translocation (Advances in DNA methylation: 5-hydroxymethylcytosine revisited, 2011).
Fine-mapping and extensive sequencing led to the identification of TET2 mutations in a variety of myeloid malignancies (Mutation in TET2 in myeloid cancers, 2009), including chronic myeloproliferative neoplasms (MPN), MDS (Acquired mutations in TET2 are common in myelodysplastic syndromes, 2009), primary and secondary AML (Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia, 2013), and chronic myelomonocytic leukemia (CMML) (An evolutionary perspective on chronic myelomonocytic leukemia, 2013).
In the AML cohort, IDH1/2 mutations are mutually exclusive with mutations in TET2 and TET2 loss-of-function mutations are associated with similar epigenetic defects, as IDH1/2 mutants
(Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation, 2010).
(A mechanistic overview of TET-mediated 5-methylcytosine oxidation, 2013)
TET2 is a key target of miR-22 in MDS and hematological malignancies and the downregulation of TET2 protein also correlated with poor clinical outcomes and miR-22 overexpression in MDS patients. So, aberrations in the miR-22/TET2 regulatory network are common in hematopoietic malignancies (The Oncogenic MicroRNA miR-22 Targets the TET2 Tumor Suppressor to Promote Hematopoietic Stem Cell Self-Renewal and Transformation, 2013).
TET2 is a key target of miR-22 in MDS and hematological malignancies and the downregulation of TET2 protein also correlated with poor clinical outcomes and miR-22 overexpression in MDS patients. So, aberrations in the miR-22/TET2 regulatory network are common in hematopoietic malignancies(MicroRNA-Antagonism Regulates Breast Cancer Stemness and Metastasis via TET-Family-Dependent Chromatin Remodeling, 2013).
METABOLOEPIGENETICS
Diet and Energy Metabolism Affect Gene Expression, which Influences Human Health and Disease
The importance of food is not restricted to its nutritional content, but also to the epigenetic regulation of gene expression profiles.
The relative abundance of energy metabolites allows a cell to sense its energetic state. In fact, the reduction in NADPH and ATP levels induces DNA demethylation through TCA cycle, suggesting a role of epigenetics as a mechanistic link between energy metabolism and control of gene expression.
The effect of diet and energy metabolism on DNA methylation has been evolutionary conserved. A particularly good example is a honeybee colony where the vast majority of females are infertile worker bees with usually just one fertile queen per hive. The queen is genetically identical to the worker bees, but destined to become a queen as a larva when she is fed relatively high levels of a substance produced by nurse bees called royal jelly. Royal jelly decreases DNA methylation in order to endow queens with their ability to reproduce via fully developed ovaries and other profound physical and behavioral changes including increased body size and longevity.
(Metaboloepigenetics: interrelationships between energy metabolism and epigenetic control of gene expression, 2012)
