TET2 Gene

TET2 also called "Tet Methylcytosine Dioxygenase 2" (TET is the acronym for "Ten-Eleven Translocation"), is a protein-coding gene located on chromosome 4q24. Two variants encoding different isoforms have been found for this gene.

The protein encoded by this gene, TET2, is one of the three proteins of the TET (ten-eleven translocation) family. The protein is an evolutionarily conserved methylcytosine dioxygenase, an enzyme that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation (Solary E et al. 2014). The conversion of 5mC to 5hmC, 5fC and 5caC is likely the first step in cytosine demethylation. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome that plays an important role in transcriptional regulation.

TET dioxygenases require 2-oxoglutarate, oxygen and Fe(II) for their activity, which is enhanced in the presence of ascorbic acid. TET2 is the most expressed TET gene in hematopoietic tissues, especially in hematopoietic stem cells. Analysis of Tet2 knockout mice, which are viable and fertile, showed that Tet2 functions as a tumor suppressor whose haploinsufficiency triggers myeloid and lymphoid transformations (Chiba S 2017).

Defects in the TET2 gene have been associated with various myeloproliferative disorders. Diseases associated with TET2 include immune dysregulation syndromes.

Cases of autosomal recessive germline TET2 deficiency have been reported in children with an immune dysregulation syndrome characterized by susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphomas of B cells (n = 2) or T cells (Stremenova Spegarova J et al. 2020). Evidence included homozygous germline mismatch or nonsense mutations in the TET2 gene. The mutant TET2 protein was absent or had an enzymatic defect related to 5-hydroxymethylation activity (Stremenova Spegarova J et al 2020) . An important paralog of this gene is TET3.

1. Chiba S (2017) Dysregulation of TET2 in hematologic malignancies. Int J Hematol105:17-22.
2. Cull AH et al (2017) Tet2 restrains inflammatory gene expression in macrophages. Exp Hematol 55:56-70
3. Feng Y et al (2019) TET2 Function in Hematopoietic Malignancies, Immune Regulation, and DNA Repair. Front Oncol 9:210.
4. Solary E et al (2014) The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia 28:485-496.
5. Stremenova Spegarova J et al (2020) Germline TET2 loss of function causes childhood immunodeficiency and lymphoma. Blood136:1055-1066.
6. Wang L et al (2018) TET2 coactivates gene expression through demethylation of enhancers. Sci Adv 4:eaau6986.