Tet methylcytosine dioxygenase 2

Tet methylcytosine dioxygenase 2 (TET2) is a human gene.[5] It resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies.

TET2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4NM6, 5DEU, 5D9Y
Identifiers
Aliases	TET2, KIAA1546, MDS, tet methylcytosine dioxygenase 2, Tet methylcytosine dioxygenase 2
External IDs	OMIM: 612839 MGI: 2443298 HomoloGene: 49498 GeneCards: TET2
Gene location (Human) Chr. Chromosome 4 (human)[1] Band 4q24 Start 105,145,875 bp[1] End 105,279,816 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3|3 G3 Start 133,463,679 bp[2] End 133,545,139 bp[2]
Gene ontology Molecular function • GO:0001948 protein binding • metal ion binding • oxidoreductase activity • dioxygenase activity • zinc ion binding • DNA binding • ferrous iron binding • methylcytosine dioxygenase activity • iron ion binding Cellular component • cell nucleus Biological process • 5-methylcytosine catabolic process • cell cycle • response to organic cyclic compound • oxidation-reduction process • protein O-linked glycosylation • myeloid cell differentiation • positive regulation of transcription from RNA polymerase II promoter • DNA demethylation • histone H3-K4 trimethylation • chromatin organization • oxidative demethylation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	54790	214133
Ensembl	ENSG00000168769	ENSMUSG00000040943
UniProt	Q6N021	Q4JK59
RefSeq (mRNA)	NM_001127208 NM_017628	NM_001040400 NM_145989 NM_001346736
RefSeq (protein)	NP_001120680 NP_060098	NP_001035490 NP_001333665
Location (UCSC)	Chr 4: 105.15 – 105.28 Mb	Chr 3: 133.46 – 133.55 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Clinical significance

The most striking outcome of aberrant TET activity is its association with the development of cancer.

Mutations in this gene were first identified in myeloid neoplasms with deletion or uniparental disomy at 4q24.[6] TET2 may also be a candidate for active DNA demethylation, the catalytic removal of the methyl group added to the fifth carbon on the cytosine base.

Damaging variants in TET2 were attributed as the cause of several myeloid malignancies around the same time as the protein’s function was reported for TET-dependent oxidation.[7][8][9][10][11][12][13] Not only were damaging TET2 mutations found in disease, but the levels of 5hmC were also affected, linking the molecular mechanism of impaired demethylation with disease [75]. [14] In mice the depletion of TET2 skewed the differentiation of haematopoietic precursors [14], as well as amplifying the rate of haematopoietic or progenitor cell renewal. [15][16][17][18]

Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML).[19]

TET2 mutations have prognostic value in cytogenetically normal acute myeloid leukemia (CN-AML). "Nonsense" and "frameshift" mutations in this gene are associated with poor outcome on standard therapies in this otherwise favorable-risk patient subset.[20]

Loss-of-function TET2 mutations may also have a possible causal role in atherogenesis as reported by Jaiswal S. et al. [21] Loss-of-function due to somatic variants are frequently reported in cancer, however homozygous germline loss-of-function has been shown in humans, causing childhood immunodeficiency and lymphoma.[22] The phenotype of immunodeficiency, autoimmunity and lymphoproliferation highlights requisite roles of TET2 in the human immune system.

Function

TET2 encodes a protein that catalyzes the conversion of the modified DNA base methylcytosine to 5-hydroxymethylcytosine.

The first mechanistic reports showed tissue-specific accumulation of 5-hydroxymethylcytosine (5hmC) and the conversion of 5mC to 5hmC by TET1 in humans in 2009.[23][24] In these two papers, Kriaucionis and Heintz [23] provided evidence that a high abundance of 5hmC can be found in specific tissues and Tahiliani et al. [24] demonstrated the TET1-dependent conversion of 5mC to 5hmC. A role for TET1 in cancer was reported in 2003 showing that it acted as a complex with MLL (myeloid/lymphoid or mixed-lineage leukaemia 1) (KMT2A), [25][26] a positive global regulator of gene transcription that is named after its role cancer regulation. An explanation for protein function was provided in 2009 [27] via computational search for enzymes that could modify 5mC. At this time, methylation was known to be crucial for gene silencing, mammalian development, and retrotransposon silencing. The mammalian TET proteins were found to be orthologues of Trypanosoma brucei base J-binding protein 1 (JBP1) and JBP2. Base J was the first hypermodified base that was known in eukaryotic DNA and had been found in Trypanosoma brucei DNA in the early 1990s,[28] although the evidence of an unusual form of DNA modification goes back to at least the mid 1980s.[29]

In two back-to-back Science articles, firstly [30] it was demonstrated that (1) TET converts 5mC to 5fC and 5caC, and (2) 5fC and 5caC are both present in mouse embryonic stem cells and organs, and secondly [31] that (1) TET converts 5mC and 5hmC to 5caC, (2) the 5caC can then be excised by thymine DNA glycosylase (TDG), and (3) depleting TDG causes 5caC accumulation in mouse embryonic stem cells.

In general terms, DNA methylation causes specific sequences to become inaccessible for gene expression. The process of demethylation is initiated through modification of the 5mC to 5hmC, 5fC, etc. To return to the unmodified form of cytosine (C), the site is targeted for TDG-dependent base excision repair (TET–TDG–BER) [30][32][33]. The “thymine” in TDG (thymine DNA glycosylase) might be considered a misnomer; TDG was previously known for removing thymine moieties from G/T mismatches.

The process involves hydrolysing the carbon-nitrogen bond between the sugar-phosphate DNA backbone and the mismatched thymine. Only in 2011, two publications [30] [31] demonstrated the activity for TDG as also excising the oxidation products of 5-methylcytosine. Furthermore, in the same year [32] it was shown that TDG excises both 5fC and 5caC. The site left behind remains abasic until it is repaired by the base excision repair system. The biochemical process was further described in 2016 [33] by evidence of base excision repair coupled with TET and TDG.

In simple terms, TET–TDG–BER produces demethylation; TET proteins oxidise 5mC to create the substrate for TDG-dependent excision. Base excision repair then replaces 5mC with C.

WIT pathway

TET2 is mutated in 7%–23% of AML patients. Importantly, TET2 is mutated in a mutually exclusive manner with WT1, IDH1, and IDH2.[34] TET2 can be recruited by WT1, a sequence-specific zinc finger transcription factor, to its target genes and activates WT1-target genes by converting methylcytosine into 5-hydroxymethylcytosine at the genes’ promoters.[35] The WIT pathway might also be more broadly involved in suppressing tumor formation, as a number of non-hematopoietic malignancies appear to harbor mutations of WIT genes in a non-exclusive manner.[36]

References

1. GRCh38: Ensembl release 89: ENSG00000168769 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000040943 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Tet methylcytosine dioxygenase 1". Retrieved 1 September 2012.
6. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, et al. (July 2009). "Acquired mutations in TET2 are common in myelodysplastic syndromes". Nature Genetics. 41 (7): 838–42. doi:10.1038/ng.391. PMID 19483684.
7. Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, et al. (May 2009). "Mutation in TET2 in myeloid cancers". The New England Journal of Medicine. 360 (22): 2289–301. doi:10.1056/NEJMoa0810069. PMID 19474426.
8. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, et al. (July 2009). "Acquired mutations in TET2 are common in myelodysplastic syndromes". Nature Genetics. 41 (7): 838–42. doi:10.1038/ng.391. PMID 19483684.
9. Abdel-Wahab O, Mullally A, Hedvat C, Garcia-Manero G, Patel J, Wadleigh M, et al. (July 2009). "Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies". Blood. 114 (1): 144–7. doi:10.1182/blood-2009-03-210039. PMID 19420352.
10. Jankowska AM, Szpurka H, Tiu RV, Makishima H, Afable M, Huh J, et al. (June 2009). "Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms". Blood. 113 (25): 6403–10. doi:10.1182/blood-2009-02-205690. PMID 19372255.
11. Tefferi A, Pardanani A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, et al. (May 2009). "TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis". Leukemia. 23 (5): 905–11. doi:10.1038/leu.2009.47. PMC 4654629. PMID 19262601.
12. Tefferi A, Levine RL, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, et al. (May 2009). "Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates". Leukemia. 23 (5): 900–4. doi:10.1038/leu.2009.37. PMID 19262599.
13. Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, et al. (July 2009). "Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML". Leukemia. 23 (7): 1343–5. doi:10.1038/leu.2009.59. PMID 19295549.
14. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. (December 2010). "Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2". Nature. 468 (7325): 839–43. doi:10.1038/nature09586. PMC 3003755. PMID 21057493.
15. Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. (July 2011). "Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation". Cancer Cell. 20 (1): 11–24. doi:10.1016/j.ccr.2011.06.001. PMC 3194039. PMID 21723200.
16. Quivoron C, Couronné L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, et al. (July 2011). "TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis". Cancer Cell. 20 (1): 25–38. doi:10.1016/j.ccr.2011.06.003. PMID 21723201.
17. Ko M, Bandukwala HS, An J, Lamperti ED, Thompson EC, Hastie R, et al. (August 2011). "Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice". Proceedings of the National Academy of Sciences of the United States of America. 108 (35): 14566–71. doi:10.1073/pnas.1112317108. PMC 3167529. PMID 21873190.
18. Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, et al. (October 2011). "Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies". Blood. 118 (17): 4509–18. doi:10.1182/blood-2010-12-325241. PMC 3952630. PMID 21803851.
19. Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. (December 2010). "Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2". Nature. 468 (7325): 839–43. doi:10.1038/nature09586. PMC 3003755. PMID 21057493.
20. Metzeler KH, Maharry K, Radmacher MD, Mrózek K, Margeson D, Becker H, et al. (April 2011). "TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study". Journal of Clinical Oncology. 29 (10): 1373–81. doi:10.1200/JCO.2010.32.7742. PMC 3084003. PMID 21343549.
21. Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. (July 2017). "Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease". The New England Journal of Medicine. 377 (2): 111–121. doi:10.1056/NEJMoa1701719. PMC 6717509. PMID 28636844.
22. Stremenova Spegarova J, Lawless D, Mohamad SM, Engelhardt KR, Doody GM, Shrimpton J, et al. (June 2020). "Germline TET2 Loss-Of-Function Causes Childhood Immunodeficiency And Lymphoma". Blood: blood.2020005844. doi:10.1182/blood.2020005844. PMID 32518946.
23. Kriaucionis S, Heintz N (May 2009). "The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain". Science. 324 (5929): 929–30. doi:10.1126/science.1169786. PMC 3263819. PMID 19372393.
24. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. (May 2009). "Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1". Science. 324 (5929): 930–5. doi:10.1126/science.1170116. PMC 2715015. PMID 19372391.
25. Lorsbach RB, Moore J, Mathew S, Raimondi SC, Mukatira ST, Downing JR (March 2003). "TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23)". Leukemia. 17 (3): 637–41. doi:10.1038/sj.leu.2402834. PMID 12646957.
26. Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y (July 2002). "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 Research. 62 (14): 4075–80. PMID 12124344.
27. Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, et al. (May 2009). "Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1". Science. 324 (5929): 930–5. doi:10.1126/science.1170116. PMID 19372391.
28. Gommers-Ampt JH, Van Leeuwen F, de Beer AL, Vliegenthart JF, Dizdaroglu M, Kowalak JA, et al. (December 1993). "beta-D-glucosyl-hydroxymethyluracil: a novel modified base present in the DNA of the parasitic protozoan T. brucei". Cell. 75 (6): 1129–36. doi:10.1016/0092-8674(93)90322-h. PMID 8261512.
29. Bernards A, van Harten-Loosbroek N, Borst P (May 1984). "Modification of telomeric DNA in Trypanosoma brucei; a role in antigenic variation?". Nucleic Acids Research. 12 (10): 4153–70. doi:10.1093/nar/12.10.4153. PMID 6328412.
30. He YF, Li BZ, Li Z, Liu P, Wang Y, Tang Q, et al. (September 2011). "Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA". Science. 333 (6047): 1303–7. doi:10.1126/science.1210944. PMC 3462231. PMID 21817016.
31. Ito S, Shen L, Dai Q, Wu SC, Collins LB, Swenberg JA, et al. (September 2011). "Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine". Science. 333 (6047): 1300–3. doi:10.1126/science.1210597. PMC 3495246. PMID 21778364.
32. Maiti A, Drohat AC (October 2011). "Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites". The Journal of Biological Chemistry. 286 (41): 35334–8. doi:10.1074/jbc.c111.284620. PMID 21862836.
33. Weber AR, Krawczyk C, Robertson AB, Kuśnierczyk A, Vågbø CB, Schuermann D, et al. (March 2016). "Biochemical reconstitution of TET1-TDG-BER-dependent active DNA demethylation reveals a highly coordinated mechanism". Nature Communications. 7 (1): 10806. doi:10.1038/ncomms10806. PMID 26932196.
34. Rampal R, Alkalin A, Madzo J, Vasanthakumar A, Pronier E, Patel J, et al. (December 2014). "DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia". Cell Reports. 9 (5): 1841–1855. doi:10.1016/j.celrep.2014.11.004. PMC 4267494. PMID 25482556.
35. Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, et al. (February 2015). "WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation". Molecular Cell. 57 (4): 662–673. doi:10.1016/j.molcel.2014.12.023. PMC 4336627. PMID 25601757.
36. Sardina JL, Graf T (February 2015). "A new path to leukemia with WIT". Molecular Cell. 57 (4): 573–574. doi:10.1016/j.molcel.2015.02.005. PMID 25699704.

Further reading

• Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, Massop M, et al. (July 2009). "Acquired mutations in TET2 are common in myelodysplastic syndromes". Nature Genetics. 41 (7): 838–42. doi:10.1038/ng.391. PMID 19483684.
• Ko M, Huang Y, Jankowska AM, Pape UJ, Tahiliani M, Bandukwala HS, et al. (December 2010). "Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2". Nature. 468 (7325): 839–43. doi:10.1038/nature09586. PMC 3003755. PMID 21057493.
• Metzeler KH, Maharry K, Radmacher MD, Mrózek K, Margeson D, Becker H, et al. (April 2011). "TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study". Journal of Clinical Oncology. 29 (10): 1373–81. doi:10.1200/JCO.2010.32.7742. PMC 3084003. PMID 21343549.