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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TET enzymes and key signalling pathways: Crosstalk in embryonic development and cancer
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“Therefore, TET enzymes activities are important in several stages of cell differentiation in tissue development, and any dysregulation, can lead to complications and loss of specific functions in each cellular context [20-22].”
Background
Ara-C elicits apoptosis and inhibits proliferation of human lymphoblastic leukemia Nalm6 cell lines by down regulation of HDAC3 and DNMT3B and up regulation of DNMT3A
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DNA Methylation in Eukaryotes: Regulation and Function
Niller, H. H., Demcsák, A., & Minárovits, J. (2018) · Springer eBooks · doi:10.1007/978-3-319-50542-8_24 · Cited by 2
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Digitalis purpurea Improve Obesity Inducing Alternation of Cardiac Infarction: A Meta Analysis
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“This accumulation encourages the production of toxic metabolites (such as ceramide and diacylglycerol), which in turn increases the number of cells that perish [69,70].”
Background
TET2, tumor control, and CAR T cell hyperproliferation
Dash, B., & Hogan, P. G. (2023) · Trends in cancer · doi:10.1016/j.trecan.2023.04.009 · Cited by 1
Epigenetics of transgenerational inheritance of disease
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A review on Epigenome Editing using CRISPR-based Tools to Rejuvenate Skin Tissues
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Epigenetics of Alzheimer’s Disease: Past, Present and Future
Adiga, D., Eswaran, S., Sriharikrishnaa, S., Khan, N. G., Kabekkodu, S. P., & Kumar, D. (2023) · BENTHAM SCIENCE PUBLISHERS eBooks · doi:10.2174/9789815136142123010005 · Cited by 1
Effect of Vitamin C on Cancer Process
HEMDAN, O. A. M., Girgin, G., & Baydar, T. (2024) · Hacettepe University Journal of the Faculty of Pharmacy · doi:10.52794/hujpharm.1484625 · Cited by 1
TET3 Protein Represses Proliferation of the MG-63 Human Osteosarcoma Cell Line by Regulating DNA Demethylation: an Epigenetic Study
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Unveiling the Therapeutic Promise of Epigenetics in Vascular Cognitive Impairment and Vascular Dementia
Selvaraji, S., Mosberger, J., Fann, D. Y., Lai, M. K. P., Chen, C., & Arumugam, T. V. (2025) · Aging and Disease · doi:10.14336/ad.2025.0010 · Cited by 1
“On the other hand, active DNA demethylation occurs in both dividing and non-dividing cells where it involves catalytic activity to remove methylated cytosine [83].”
Influential
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PARP inhibition increases sensitivity to cisplatin in non-small-cell lung carcinoma via the induction of TET-dependent hydroxymethylation
Grdović, N., Tolić, A., Jovanović, M., Rajić, J., Đorđević, M., Stojanović, M., Hadžić, S., Marković, T., Sarić, A., Dinić, S., et al. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1677261 · Cited by 1
“Decreased expression of TET proteins and lower 5hmC levels are hallmarks of many cancer types, including lung cancer (Rasmussen and Helin, 2016; Yang et al., 2013).”
A tunable, ultrasensitive threshold in enzymatic activity governs the DNA methylation landscape
Bonsu, K., Laszik, N., Trinh, A., Downing, T. L., & Read, E. L. (2026) · Biophysical Journal · doi:10.1016/j.bpj.2026.03.013 · Cited by 1
The TET2 Expression Level Correlates with a Short Relapse Time in Glioblastoma Multiforme
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Ten‐eleven translocation methylcytosine dioxygenase 3‐loaded microspheres penetrate neurons in vitro causing active demethylation and neurite outgrowth
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“Tet1, Tet2, and Tet3 have been found to iteratively oxidize 5‐methylcytosine (5mC) to 5‐hydroxymethylcytosine (5hmC), 5‐formylcytosine (5fC), and 5‐carboxycytosine (5caC), respectively, allowing cell‐cycle‐independent removal of DNA methylation (Rasmussen & Helin, 2016).”
Background
Features of epileptiform activity in patients with diagnosed glioblastoma: from genetic and biochemical mechanisms to clinical aspects
Tyagunova, E. E., Захаров, А. С., Иванович, Г. А., Доброхотова, В. З., Shlapakov, T. I., Козлов, В. В., Korotkova, N. V., & Tyagunova, T. E. (2022) · Head and neck tumors (HNT) · doi:10.17650/2222-1468-2022-12-3-102-113 · Cited by 1
Methylomic change in TET1 and TET2 promoters is increased in children with acute lymphocytic leukemia
Refaai, R., Ragab, D., Guirgis, A. A., & Khalil, H. (2023) · doi:10.54646/bjcr.2023.10 · Cited by 1
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Lund, G., & Zaina, S. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.65409-0 · Cited by 1
O Diabetes Mellitus induz alterações epigenéticas no gene Slc2a4 em músculo esquelético que se relacionam com a repressão do gene, e que podem ser revertidas pela insulinoterapia ou pelo resveratrol.
Yonamine, C. Y. (2018) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.42.2018.tde-21022018-172243 · Cited by 1
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Gervásio, V. S. O. D. S. (2018) · doi:10.14393/ufu.di.2018.573 · Cited by 1
TET3 IMPACTS CARDIAC FIBROSIS PARTIALLY VIA REGULATION OF DNA DAMAGE RESPONSE
Rath, S. K. (2020) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-7851 · Cited by 1
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Murison, K., & Michod, D. (2020) · Wiley eBooks · doi:10.1002/9780470015902.a0028374 · Cited by 1
Agents Which Act Directly on DNA
Todd, A., Groundwater, P. W., & Gill, J. H. (2017) · Wiley eBooks · doi:10.1002/9781118696194.ch2.1 · Cited by 1
Synthetic lethal targeting of TET2 -mutant hematopoietic stem and progenitor cells by XPO1 inhibitorsPreprint
Jing, C., Prutsch, N., He, S., Zimmerman, M. W., Landesman, Y., & Look, A. T. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.10.12.511957 · Cited by 1
The epigenetic Oct4 gene regulatory network: stochastic analysis of different cellular reprogramming approachesPreprint
Bruno, S., & Vecchio, D. D. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.03.01.530689 · Cited by 1
“…H3K9me3 [25, 37–39], TET enzyme recognizes CpGme dinucleotides and converts methylated CpG to carbolxylcytosine through multiple intermediate forms [40, 41], none of which is recognized by DNMT1, the enzyme responsible for copying the CpGme pattern on the nascent DNA strand during DNA replication…”
Background
Data from TET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling
Zhang, X., Li, S., He, J., Jin, Y., Zhang, R., Dong, W., Lin, M., Yang, Y., Tian, T., Zhou, Y., et al. (2023) · doi:10.1158/0008-5472.c.6513850.v1 · Cited by 1
Mutant IDH uncouples p53 from target gene regulation to disable tumor suppressionPreprint
Martin, C. P., Sullivan, W. B., Brinkman, J. A., Scoville, D. M., Yashinskie, J. J., Tian, S., Mezzadra, R., Ho, Y.-J., Koche, R. P., Baslan, T., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.30.615916 · Cited by 1
Enhanc(er)ing Skin Stem Cells
Wang, Y., & Sen, G. L. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.09.003 · Cited by 1
“5-mc can be oxidized to 5-hmc through the Ten-eleven translocation (TET 1–3) family of enzymes (Rasmussen and Helin, 2016) and is thought to be an intermediate base during 5-mc demethyation that may have roles in regulating gene expression.”
Background

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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