PreprintCited by 1,040Epigenetics and DNA MethylationGenomics and Chromatin DynamicsCancer-related gene regulation

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Role of TET enzymes in DNA methylation, development, and cancer

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Rasmussen, Kasper Dindler, Helin, Kristian·2016·Genes & Development

DOI 10.1101/gad.276568.115PMC PMC4826392

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Abstract

The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression, and DNA methylation abnormalities are often observed in diseases. The ten eleven translocation (TET) enzymes oxidize 5-methylcytosines (5mCs) and promote locus-specific reversal of DNA methylation. TET genes, and especially TET2 , are frequently mutated in various cancers, but how the TET proteins contribute to prevent the onset and maintenance of these malignancies is largely unknown. Here, we highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. In addition, we discuss some of the key outstanding questions in the field.

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“Thus, it was remarkable when ten eleven translocation protein 1 (TET1) was discovered and shown to be able to modify methylcytosine and potentially erase DNAmethylation (Tahiliani et al. 2009).”
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Background
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Background
Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
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“6-fold) substrates compared with the initial oxidation reaction of 5mC (Ito et al. 2011; Hu et al. 2015).”
Background
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“Subsequent to the discovery of oxidized 5mC bases, it was demonstrated that TDG has no effect on 5hmC but shows robust recruitment and in vitro catalytic activity toward 5fC and 5caC (He et al. 2011; Maiti and Drohat 2011; Spruijt et al. 2013).”
BackgroundInfluential
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“By comparison, the products of further TET-mediated oxidation, 5fC and 5caC, are observed at ∼10-fold to 100-fold lower levels than 5hmC and often close to or under the detection limit (Kriaucionis and Heintz 2009; Globisch et al. 2010; Szwagierczak et al. 2010; He et al. 2011; Ito et al. 2011; Pfaffeneder et al. 2011…”
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Background
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Background
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Background
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Background
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Background
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Background
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Method
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Background
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BackgroundInfluential
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BackgroundInfluential
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Background
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“Previous research suggests that DNMT3L interacts with DNMT3A/B to facilitate methylation [27], whereas proteins of the TET family exert an opposing effect [28, 29].”
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Association between ten-eleven methylcytosine dioxygenase 2 genetic variation and viral load in people with HIV
Murray, D. D., Grund, B., MacPherson, C. R., Ekenberg, C., Zucco, A. G., Reekie, J., Domínguez, L., Leung, P., Fusco, D. N., Gras, J., et al. (2022) · AIDS · doi:10.1097/qad.0000000000003427 · Cited by 4
Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy
de Nys, R., van Eyk, C. L., Ritchie, T., Møller, R. S., Scheffer, I. E., Marini, C., Bhattacharjee, R., Kumar, R., & Gécz, J. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-02783-5 · Cited by 4
Experimental Varicocele Impairs DNA Methylation and Demethylation in Germ Cells, TESE, and Epididymal Spermatozoa, Impacting Active DNA Demethylation in Zygotes
Moshari, S., Razi, M., Nasr‐Esfahani, M. H., Tavalaee, M., & Hajian, M. (2024) · Reproductive Sciences · doi:10.1007/s43032-024-01651-3 · Cited by 4
“Several articles have shown that ten-eleven-translocation (TET) proteins are actively involved in oxidizing 5mC to 5hmC in the testicular tissue and at early stages after oocyte fertilization which is known as "active DNA demethylation (ADD)" [18].”
DNA demethylation pattern of in-vitro fertilized and cloned porcine pronuclear stage embryos
Nie, X., Liu, Q., Wang, R., Sheng, W., Li, X., Zhang, M., Jin, Y., Zhao, L., Hou, D., Yang, N., et al. (2017) · Clinica Chimica Acta · doi:10.1016/j.cca.2017.07.025 · Cited by 4
Technologies and applications for the assessment of 5-hydroxymethylcytosine
Jurkowski, T. P. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819414-0.00013-6 · Cited by 4
Tet1 is not required for myeloid leukemogenesis by MLL-ENL in novel mouse models
Ono, R., Masuya, M., Inoue, N., Shinmei, M., Ishii, S., Maegawa, Y., Maharjan, B. D., Katayama, N., & Nosaka, T. (2021) · PLoS ONE · doi:10.1371/journal.pone.0248425 · Cited by 4
“Tet1 has a catalytic dioxygenase domain consisting of a cysteine (Cys)-rich region and a double-stranded β-helix (DSBH) at the C-terminal part [8].”
Background
Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive demethylation in mammalsPreprint
Mulholland, C. B., Nishiyama, A., Ryan, J., Nakamura, R., Yiğit, M., Glück, I. M., Trummer, C., Qin, W., Bartoschek, M. D., Traube, F. R., et al. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/321604 · Cited by 4
Epigenetic therapy of cancer
Avendaño, C., & Menéndez, J. C. (2023) · Medicinal Chemistry of Anticancer Drugs · doi:10.1016/b978-0-12-818549-0.00019-4 · Cited by 4
Epigenetic regulation of Hutchinson-Gilford progeria syndrome: from molecular mechanisms to targeted interventions
Liu, X., Yang, S., Jiang, J., Dong, S., & Zhang, Y. (2025) · Oral Science and Homeostatic Medicine · doi:10.26599/oshm.2025.9610013 · Cited by 3
Assessing the impact of TET2 and TET3 deletion in TCRalpha and TCRbeta repertoire in murine CD4 T cells in physiological and pathophysiological conditions
Äijö, T., Gioulbasani, M., Valenzuela, J. E., & Tsagaratou, A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1638500 · Cited by 3
“Instead, secondary mutations are required to result in cancer emergence (9, 14).”
Epigenetics in intestinal stem cells: Molecular mechanisms underpinning the guardians of homeostasis in health and aging-related senescence
Liu, B., Wang, Y., Chu, X., Wang, J., Pan, T., Xie, L., Abankwah, J. K., & Bian, Y. (2025) · Pathology - Research and Practice · doi:10.1016/j.prp.2025.156187 · Cited by 3
Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation
Leesang, T. E., Brabson, J. P., Yap, Y. S., Barbieri, D. A., Klimas, A. S., Pinzone, J., Ahearn, E. L., Lam, M. Q., Lyon, P. D., Swirski, A., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116379 · Cited by 3
“Previous studies in murine models have shown that Tet2 and Tet3 both act as tumor suppressors of the myeloid lineage, 4,12,45 and TET2 mutation 5 or decreased expression of either TET2 or TET3 is associated with more aggressive disease in patients with AML.”
Epigenetics and disease progression in neuroendocrine neoplasms
Lobato, E. C., Lafranchi, A., Freitas-Castro, F., Fagundes, G. F. C., Sadiković, B., Lines, K. E., & Almeida, M. Q. (2026) · Endocrine Reviews · doi:10.1210/endrev/bnag005 · Cited by 3
Structural basis of the promiscuity of the unusual Fe(II) and 2-oxoglutarate dependent human aspartate/asparagine-β-hydroxylase
de Munnik, M., Brasnett, A., Zhou, T.-K., Myers, W., Wang, Y.-C., Chatterjee, K., Tumber, A., Marshall, S. A., Simon, P. S., Aller, P., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-69425-w · Cited by 4
Epigenetically regulated pancreatic GABA-somatostatin signaling underlies gestational diabetes–induced glucose intolerance in offspring
Zhu, H., Luo, S., Liu, C., Cheng, Y., Ren, Z., Mo, J., Cao, C., Cui, J., Yan, J., Jiang, Y., et al. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.adx8909 · Cited by 3
DNMT3A in cancer: from epigenetic writer to oncogenic driver
Dupas, T., Gautreau, E., Josianne, C., Raynal, N. J. ‐., & McGraw, S. (2026) · Clinical Epigenetics · doi:10.1186/s13148-026-02127-8 · Cited by 3
“The role of these proteins in cancer has been widely reviewed [68, 69].”
THAP 3 recruits SMYD 3 to OXPHOS genes and epigenetically promotes mitochondrial respiration in hepatocellular carcinoma
Wang, Z., Wang, J., Liu, F., Sun, S., Zheng, Q., Hu, X., Yin, Z., Xie, C., Wang, H., Wang, T., et al. (2024) · FEBS Letters · doi:10.1002/1873-3468.14889 · Cited by 4
“Mechanistically, TFs can recruit epigenetic enzymes and guide them to speciﬁc genomic loci, allowing them to precisely modify genomic DNA or histone tails at target genes [13,14].”
Background
The physiological functions of ascorbate in the development of cancer
Agathocleous, M. (2025) · Disease Models & Mechanisms · doi:10.1242/dmm.052201 · Cited by 4
The role of pioneering transcription factors, chromatin accessibility and epigenetic reprogramming in oncogenic viruses
Kgatle, M. M., Mbambara, S., Khoza, L., Fadebi, O. O., Mashamba-Thompson, T. P., & Sathekge, M. M. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1602497 · Cited by 4
“Reduced TET activity can result in hypermethylation of tumor suppressor genes, contributing to cancer development (Thienpont et al., 2016; Rasmussen and Helin, 2016).”
Therapeutic Potential of High Dose Vitamin C in Cancer: Mechanisms, Clinical Evidence and Future Directions
Singh, R., Parchwani, D. N., Sharma, G., & Sharma, P. (2025) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-025-01341-0 · Cited by 3
“Conversely, TET enzymes (TET1, TET2, and TET3) belonging to the α-KGDD family work to demethylate DNA by oxidizing 5mC to 5-hydroxymethylcytosine (5hmC) with simultaneous generation of intermediates, thus reactivating genes silenced by hypermethylation [114, 115].”
Antioxidant and antihypoxic properties of neuroprotective drugs
Poloznikov, A. A., Smirnova, N. A., Khristichenko, A. Y., Hushpulian, D. M., Nikulin, S. V., Tishkov, V. I., Gaisina, I. N., & Gazaryan, I. G. (2016) · Russian Chemical Bulletin · doi:10.1007/s11172-016-1687-2 · Cited by 3
The epigenetics of multiple sclerosis
Christensen, T., & Muchardt, C. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-813796-3.00005-5 · Cited by 3
Epigenetic Enzymes and Drawbacks of Conventional Therapeutic Regimens
Ganai, S. A. (2019) · Springer eBooks · doi:10.1007/978-981-13-8019-8_2 · Cited by 3
Tet2-mediated DNA demethylation regulates the proliferation and apoptosis of human leukemia K562 cells
Qiao, Y., Zhou, Y.-H., Yang, H., He, Z., & Fan, A. (2023) · Cellular and Molecular Biology · doi:10.14715/cmb/2023.69.3.4 · Cited by 4
“The frequency of Tet2 mutations in patients with MDS is 6%–26%, and CMML is 20%–58%, and it is also frequently observed in primary and secondary AML (12%–32%), blastic plasmacytoid dendritic neoplasm (25%–54%) and myeloproliferative neoplasms (MPNs), such as polycythemia vera, primary myelofibrosis, and essential thro…”
Background
DNA hypomethylation in wood frog liver under anoxia and dehydration stresses
Kupakuwana, P., Singh, G., & Storey, K. B. (2024) · Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology · doi:10.1016/j.cbpb.2024.111005 · Cited by 6
Prognostic and functional role of the nuclear export receptor 1 (XPO1) in gastrointestinal cancers: a potential novel target?
Sokolova, V., Gruber, R., Pammer, L. M., Kocher, F., Klieser, E., Amann, A., Pichler, R., Günther, M., Ormanns, S., Neureiter, D., et al. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-10169-5 · Cited by 3
“The ten-eleven translocation (TET) protein family influences epigenetics, initiates demethylation pathways and is associated with tumorigenesis [133, 134].”
Identification of clinicopathological‐specific driver gene and genetic subtyping of colorectal cancer
Li, J., Wang, C., Yang, C., Bao, H., Li, N., Huang, X., Gong, W., Hong, X., Yin, J. C., Pang, J., et al. (2025) · Cancer Science · doi:10.1111/cas.16432 · Cited by 3
“(D) Distribution of the SNVs of PIK3CA in the MSS and MSI groups. of mismatch repair genes; 18 as a DNA methylation regulator, 19 the role of TET2 in MSI CRC is worthy of further study.”
PRAME Expression in Melanoma is Negatively Regulated by TET2-Mediated DNA Hydroxymethylation
Fang, R., Vallius, T., Zhang, A., Cura, D. V., Alicandri, F., Fischer, G. M., Draper, E. C., Xu, S., Pelletier, R. J., Wang, J., et al. (2024) · Laboratory Investigation · doi:10.1016/j.labinv.2025.104123 · Cited by 3
Espoirs et promesses de la méthylation de l’ADN et des histones comme cibles anticancéreuses
Bon, C., Erdmann, D., Halby, L., & Arimondo, P. B. (2019) · Bulletin du Cancer · doi:10.1016/j.bulcan.2019.08.001 · Cited by 3
Ivosidenib for the treatment of relapsed or refractory acute myeloid leukemia with an IDH1 mutation
Pasquier, F., Chahine, C., Marzac, C., & de Botton, S. (2020) · Expert Review of Precision Medicine and Drug Development · doi:10.1080/23808993.2020.1792286 · Cited by 3
Epigenetic Characteristics of Human Subtelomeres Vary in Cells Utilizing the Alternative Lengthening of Telomeres (ALT) Pathway
Toubiana, S., Tzur-Gilat, A., & Selig, S. (2021) · Life · doi:10.3390/life11040278 · Cited by 3
“DNA methylation is also regulated by active demethylation carried out by enzymes from the ten-eleven translocation methylcytosine dioxygenases (TET) family of proteins, and mutations in TET genes have been implicated in hypomethylated states in various cancers [45,46].”
Background
Epigenetics in precision medicine of pancreatic cancer
Kim, H. S., & Shi, J. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-823008-4.00016-0 · Cited by 3
Chromatin and Epigenetics at the Forefront: Finding Clues among Peaks
Aranda, S., Shi, Y., & Croce, L. D. (2016) · Molecular and Cellular Biology · doi:10.1128/mcb.00328-16 · Cited by 4
“That last oxidized form is finally transformed into an unmodified cytosine by the action of the thymidine-DNA glycosylase (Tdg) and the base excision repair system (39).”
Background
DNA Methylation Changes in Cancer
Thomson, J. P., & Meehan, R. R. (2017) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-319-59786-7_4 · Cited by 3
High Doses of Vitamin C and Leukemia: In Vitro Update
Mastrangelo, D., Massai, L., Fioritoni, G., Lo‐Coco, F., Noguera, N. I., & Testa, U. (2018) · InTech eBooks · doi:10.5772/intechopen.71484 · Cited by 3
“Decreased TET expression and loss of 5hmC have been observed in a wide variety of solid tumors, as well as in many hematological malignancies, including acute myeloid leukemias, myelodysplastic syndromes, and clonal hematopoiesis [114].”
Background
Vitamin C’s essential role in DNA and histone demethylation and a preclinical rationale for its therapeutic high-dose potential in renal cell carcinoma
Huang, C.-H., & Chang, C. (2019) · Annals of Translational Medicine · doi:10.21037/atm.2019.05.49 · Cited by 3
“It is well-known that DNA methylation at cytosine bases in the genome is tightly linked to gene expression and modified cytosines, resulting in a G/T mismatch, and has long been recognized as a hotspot for mutations (9).”
Background
Epigenetics of diabetic wound healing
Singh, K., & Sen, C. K. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-816413-6.00009-5 · Cited by 4
Overview of Epigenetic Signatures and Their Regulation by Epigenetic Modification Enzymes
Ganai, S. A. (2020) · Springer eBooks · doi:10.1007/978-981-15-8179-3_1 · Cited by 3
The influence of tissue spatial geometry and functional organisation on liver regeneration
Aloia, L. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.09.011 · Cited by 4
“Of note, TET1 epigenetic activity inducing cholangiocyte de-differentiation, is dependent on 2-OG [97].”
Aberrant epigenetic regulation of RARβ by TET2 is involved in cutaneous squamous cell carcinoma resistance to retinoic acid
Zhang, X., Yan, C., Chu, Z., Shi, L., Zheng, Y., Zhao, Q., Geng, S., & Guo, K. (2022) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2022.106190 · Cited by 3
Integrative Molecular Analysis of DNA Methylation Dynamics Unveils Molecules with Prognostic Potential in Breast Cancer
Mehmood, R., Alsaleh, A., Want, M. Y., Ahmad, I., Siraj, S., Ishtiaq, M., Alshehri, F. A., Naseem, M., & Yasuhara, N. (2023) · BioMedInformatics · doi:10.3390/biomedinformatics3020029 · Cited by 3
“Disruption in the activities of members of “readers”, “writers” and “erasers” of DNA methylation has been reported [25,26].”
CpG Islands and DNA Methylation
Antequera, F. (2017) · Wiley eBooks · doi:10.1002/9780470015902.a0005027.pub3 · Cited by 3

Authors: Rasmussen, K. D., & Helin, K.
Affiliations: University of Copenhagen (DK)
Corresponding author: Helin, Kristian
ORCID: Rasmussen, Kasper Dindler
Helin, Kristian
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2016-04-01
Volume: 30
Issue: 7
Pages: 733-750
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.276568.115
PMC: PMC4826392
OpenAlex: W2325267338
Cited by: 1,040
References: 162
Citations by year: 2026: 56 · 2025: 87 · 2024: 116 · 2023: 100 · 2022: 135 · 2021: 141 · 2020: 131 · 2019: 97 · 2018: 83 · 2017: 60 · 2016: 30
Type: posted content
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc
Locations: Genes & Development (publishedVersion, cc-by-nc)
PubMed Central (publishedVersion, cc-by-nc)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc)
HighWire Press Open Archive (submittedVersion)
Funders: Danish Medical Research Council (1333-00120B)
European Research Council (294666_DNAMET)
Danish Cancer Society
Danish National Research Foundation (DNRF 82)
Danish Council for Strategic Research
Novo Nordisk Foundation
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
Keywords: TET enzymes, DNA methylation, 5-methylcytosine oxidation, TET2, demethylation, cancer, developmental regulation, transcriptional regulation, gene expression
MeSH terms: Animals, Cytosine, DNA-Binding Proteins, Humans, Neoplasms, Oxidation-Reduction, Proto-Oncogene Proteins, Gene Expression Regulation, Neoplastic, DNA Methylation, Epigenesis, Genetic, Dioxygenases

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Role of TET enzymes in DNA methylation, development, and cancer

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