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Role of TET enzymes in DNA methylation, development, and cancer
Open accessAbstract
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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“Generally, 2OGO catalyze specific hydroxylation of substrates, which, in turn, leads to demethylations via other catalytic cycles or downstream pathway involving thymine-DNA-glycosylase, which catalyzed base excision with DNA base excision repair [101,120].”
From Vitamin C-Sources, Physiological Role, Kinetics, Deficiency, Use, Toxicity, and Determination (2021) · cites this paper as [120]
Experimental — accuracy not yet measuredIn the citing paper
“TET2 is frequently mutated or lost somatically in both myeloid and lymphoid malignancies63,64.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [63]
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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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“Second, TET2 mutations are frequently observed in aged healthy individuals with clonal hematopoiesis and increase the propensity to develop hematopoieticmalignancies (Busque et al. 2012; Genovese et al. 2014; Jaiswal et al. 2014; Xie et al. 2014).”
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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).”
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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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“PAEC proliferation is mediated through the activation of SMAD1/5 and is tightly regulated by the induction of inhibitors of the DNA binding family of transcription factors.”
BackgroundInfluentialEpigenetic and epitranscriptomic role of lncRNA in carcinogenesis (Review)
Dai, C., Qianjiang, H., Fu, R., Yang, H.-M., Shi, A., & Luo, H. (2025) · International Journal of Oncology · doi:10.3892/ijo.2025.5735 · Cited by 22
“Additionally, ten‑eleven translocation (TET) family proteins (TET1, TET2 and TET3) oxidize 5mC) to 5‑hydroxy‑ methylcytosine, activating DNA demethylation (39,40) (Fig.”
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DNA methylation as a regulator of intestinal gene expression
Pinho, R. M., & Maga, E. A. (2021) · British Journal Of Nutrition · doi:10.1017/s0007114521000556 · Cited by 22
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“They have the same catalytic activity and can reverse DNA methylation by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) (9).”
BackgroundEpigenetic Mechanisms in Leukemias and LymphomasPreprint
Duy, C., Béguelin, W., & Melnick, A. M. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a034959 · Cited by 23
“4 Cite this article as Cold Spring Harb Perspect Med 2020;10:a034959 erate unmodified cytosines (Maiti and Drohat 2011; Rasmussen and Helin 2016).”
BackgroundSindhu, P., Magotra, A., Sindhu, V., & Chaudhary, P. (2024) · Zygote · doi:10.1017/s0967199424000224 · Cited by 23
“Ten-eleven translocation (TET) enzymes catalyse the oxidation of 5mC, forming several intermediates such as 5-hydroxymethylcyto-sine, 5-formylcytosine and 5-carboxylcytosine before its complete conversion to cytosine (Rasmussen and Helin, 2016).”
Tahghighi, A., Seyedhashemi, E., Mohammadi, J., Moradi, A., Esmaeili, A., Pornour, M., Jafarifar, K., & Ganji, S. M. (2025) · Clinical Epigenetics · doi:10.1186/s13148-025-01844-w · Cited by 21
“The ten-eleven translocation (TET) family of enzymes facilitates aberrant DNA methylation reversal [24].”
Hashimoto, H., Zhang, X., Zheng, Y., Wilson, G. G., & Cheng, X. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw766 · Cited by 21
“Accumulating evidence supports the view that 5hmC exists as a relatively stable modification, constituting a distinct epigenetic signal (60,61) that marks lowly expressed genes, gene bodies, and intragenic regions (reviewed in (62,63)).”
BackgroundEpigenomic and Metabolomic Integration Reveals Dynamic Metabolic Regulation in Bladder Cancer
Loras, A., Segovia, C., & Ruiz-Cerdá, J. L. (2021) · Cancers · doi:10.3390/cancers13112719 · Cited by 23
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“TET2 belongs to a family of methylcytosine dioxygenases, a group of enzymes that oxidize the methyl group of 5-mC to 5-hmC and other methylcytosines, facilitating demethylation [63].”
BackgroundEpigenetic Regulations of Perineural Invasion in Head and Neck Squamous Cell Carcinoma
Hurník, P., Chyra, Z., Ševčíková, T., Štembírek, J., Trtková, K. S., Gaykalova, D. A., Buchtová, M., & Hrubá, E. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.848557 · Cited by 21
“The TET enzymes catalyze the hydroxylation of DNA 5methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and can alter the regulation of transcription (Rasmussen and Helin, 2016) when molecular oxygen is served as a substrate to convert 5-mC to 5-hmC, and 5-hmC to 5formylcytosine (5-fC) and 5-carboxycytosine (5-caC)…”
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DNA Methylation: A Target in Neuropathic Pain
Jiang, W., Tan, X.-Y., Li, J., Yu, P., & Dong, M. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.879902 · Cited by 23
“TET proteins are large (∼180–230 kDa) multidomain enzymes and include TET1, TET2, and TET3 (70), with high neuronal and low glial expression (71).”
BackgroundInfluentialEpigenetic biomarkers for animal welfare monitoring
Whelan, R., Tönges, S., Böhl, F., & Lyko, F. (2023) · Frontiers in Veterinary Science · doi:10.3389/fvets.2022.1107843 · Cited by 23
“Demethylases are encoded by the TET family of dioxygenases that oxidize 5-methylcytosine to promote the reversal of methylation marks (20).”
BackgroundZhang, J., Cao, H., Xie, J., Fan, C., Xie, Y., He, X., Liao, M., Zhang, S., & Wang, H. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-0335-1 · Cited by 21
Biamonti, G., Maita, L., & Montecucco, A. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00408 · Cited by 22
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Exploring the Characters of Non-Coding RNAs in Spermatogenesis and Male Infertility
Yan, Q., & Wang, Q. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031128 · Cited by 20
Epigenetic interplays between DNA demethylation and histone methylation for protecting oncogenesis
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FAM72, Glioblastoma Multiforme (GBM) and Beyond
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“TET2 is a key protein involved in the development and cancer regulating gene expression via oxidization of 5mCs, thereby promoting locus-specific reversal of DNA methylation [145,146].”
BackgroundBerger, M. B., Walker, A. R., Vázquez-Montelongo, E. A., & Cisneros, G. A. (2021) · Physical Chemistry Chemical Physics · doi:10.1039/d1cp03800a · Cited by 21
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“Demethylation changes to DNA can occur in two ways, active or passive pathway [56].”
BackgroundAberrant DNA methylation in multiple myeloma: A major obstacle or an opportunity?
Muylaert, C., Hemelrijck, L. A. V., Maes, A., Veirman, K. D., Menu, E., Vanderkerken, K., & Bruyne, E. D. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.979569 · Cited by 21
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“Ten-Eleven Translocation 2 (TET2), an epigenetic regulator, facilitates DNA demethylation by converting 5-methylcytosine to 5-hydroxy-methylcytosine [10,11].”
BackgroundBivalent chromatin: a developmental balancing act tipped in cancer
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“Recent evidence showed that ten-eleven translocation (TET) proteins mediate active DNA demethylation (10).”
BackgroundMutational analysis of uterine cervical cancer that survived multiple rounds of radiotherapy
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“However, we do not have solid evidence on how TET1 mutations contribute to onset and maintenance of tumors, and it is unclear whether TET1 mutations confer a selective advantage, or whether they represent inconsequential passenger mutations; this warrants further research [35].”
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“5mC is known as a silencing mark that represses gene expression (4).”
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“1B) (29–31), which belongs to the 2OG oxygenase structural superfamily, members of which have important physiological roles in humans, including in lipid metabolism (32, 33), collagen biosynthesis (34, 35), nucleic acid repair (36, 37), hypoxia sensing (38, 39), and chromatin modification (36, 40).”
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“DNA methylation is a major epigenetic modification known to cause a silencing of gene expression [84].”
BackgroundTargeting epigenetic regulation for cancer therapy using small molecule inhibitors
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“They also demonstrated that WT1 physically interacts with TET2 and TET3, and loss-of-function WT1 caused a hematopoietic differentiation phenotype similar to that observed with TET2 defects (34).”
BackgroundActive DNA demethylation of developmental cis -regulatory regions predates vertebrate origins
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“Interestingly, despite the ability of all three TET family proteins (TET1, TET2, and TET3) to oxidize methylated CGs [62], fusions of dCas9 to the catalytic domain of TET2 and TET3 have only been presented in one thesis [63] and one article [64], respectively.”
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An Assessment on Ethanol-Blended Gasoline/Diesel Fuels on Cancer Risk and Mortality
Mueller, S., Dennison, G., & Liu, S. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18136930 · Cited by 18
Chen, X., Zhu, X., Dong, J. P., Chen, F., Gao, Q., Zhang, L., Cai, D., Dong, H., Ruan, B., Wang, Y., et al. (2022) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0219 · Cited by 18
“…is mediated by ten-eleven translocation (TET) family dioxygenase enzymes in stepwise oxidation of 5-methylcytosine to 5-hydroxymethylcytosine and further oxidation products, and it is eventually completed by DNA repair processes (39), which correlate with gene transcriptional activation.”
A Lexicon of DNA Modifications: Their Roles in Embryo Development and the Germline
Zhu, Q., Stöger, R. J., & Alberio, R. (2018) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2018.00024 · Cited by 21
Li, Q., Zhang, Z., Fan, Y., & Zhang, Q. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2020.562868 · Cited by 18
“This process can be reversed by ten-eleven translocation (TET) proteins, which oxidize 5mc into 5-hydroxymethylcytosine (5hmc) and subsequently into 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in an Fe(II)- and 2-oxoglutarate-dependent dioxygenases manner (Wu and Zhang, 2014; Rasmussen and Helin, 2016).”
BackgroundEffects of Environmental Non-Essential Toxic Heavy Metals on Epigenetics During Development
Kurita, H., Ohuchi, K., & Inden, M. (2025) · Toxics · doi:10.3390/toxics13030167 · Cited by 19
“Passive demethylation occurs by the replication-dependent dilution of 5-mC in the absence of maintenance methylation [11].”
Moonlighting Enzymes at the Interface Between Metabolism and Epigenetics
van der Knaap, J. A., & Verrijzer, C. P. (2025) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-030122-044718 · Cited by 17
Liu, Y., Xin, L., Wang, S., Tan, J., Zhu, X., Chen, X., Song, J., Chen, T., & Zhai, Q. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123468 · Cited by 18
Epigenetic networks coordinate DNA methylation across the genome
Wagner, W. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.06.037 · Cited by 20
“56,73,74 For instance, TET3 plays a pivotal role in the active de-methylation of the paternal genome post-fertilization, while TET1 and TET2 have broader roles in maintaining epigenetic balance.”
CBFB-MYH11 Fusion Sequesters RUNX1 in Cytoplasm to Prevent DNMT3A Recruitment to Target Genes in AML
Liu, P., Liu, J.-P., Sun, S.-J., Gao, Y., Ai, Y., Chen, X., Sun, Y., Zhou, M., Liu, Y., Xiong, Y., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.675424 · Cited by 17
Ghosh, K. K., Chatterjee, B., Nalla, K., Behera, B., Mukherjee, A. K., & Kanade, S. R. (2022) · Chemosphere · doi:10.1016/j.chemosphere.2022.133569 · Cited by 17
Novel methylation mark and essential hypertension
Chaudhary, M. (2022) · Journal of Genetic Engineering and Biotechnology · doi:10.1186/s43141-022-00301-y · Cited by 17
“3) of proteins [27] that converts 5mC to 5-hydroxymethlycytosine (5hmC) and further to 5-formylcytosine (5fC) which subsequently is oxidised to form 5-carboxylcytosine (5caC) [1, 28].”
BackgroundEpigenomic alterations in cancer: mechanisms and therapeutic potential
Gray, J. S., Wani, S. A., & Campbell, M. J. (2022) · Clinical Science · doi:10.1042/cs20210449 · Cited by 19
El-Harakeh, M., Saliba, J. L., Aldeen, K. S., Haidar, M., El‐Hajjar, L., Awad, M. K., Hashash, J. G., Shirinian, M., & El-Sabban, M. E. (2022) · World Journal of Gastroenterology · doi:10.3748/wjg.v28.i40.5845 · Cited by 17
Palczewski, M. B., Kuschman, H. P., Hoffman, B. M., Kathiresan, V., Yang, H., Glynn, S. A., Wilson, D. L., Kool, E. T., Montfort, W. R., Chang, J. C., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56928-1 · Cited by 18
“…mechanistic studies are needed to delineate factors contributing to the differential buildup of TET substrates, these differences maypartially be a function ofdifferences inthe catalytic rates for eachof its oxidation steps,with the fi rststep, conversion of 5mC ⇒ 5hmC, being the fastest 78 .”
DNA repair and erasure of 5‐methylcytosine in vertebrates
Schomacher, L., & Niehrs, C. (2017) · BioEssays · doi:10.1002/bies.201600218 · Cited by 18
“Otherreviewscovering, forexample,TETregulationandthe roleofTET indevelopmentanddisease [15, 18, 24, 25], the roleof DNMTs [26] and GADD45 proteins in active demethylation [27, 28], as well as DNA demethylation in plants [29] are available.”
BackgroundHe, S., Wang, F., Zhang, Y., Chen, J., Liang, L., Li, Y., Zhang, M., Yang, X. Y., Pang, H., Li, Y., et al. (2019) · Cell Discovery · doi:10.1038/s41421-018-0074-6 · Cited by 17
Howard, M. J., Foley, K. G., Shock, D. D., Batra, V. K., & Wilson, S. H. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.006809 · Cited by 17
“Humans encode three TET enzymes that are nonheme Fe(II) -ketoglutarate– dependent dioxygenases that have multiple domains (7, 8).”
BackgroundPalei, S., Buchmuller, B. C., Wolffgramm, J., Muñoz‐López, Á., Jung, S., Czodrowski, P., & Summerer, D. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c01193 · Cited by 17
HDAC4 inhibition disrupts TET2 function in high-risk MDS and AML
Huang, F., Sun, J., Chen, W., He, X., Zhu, Y., Dong, H., Wang, H., Li, Z., Zhang, L., Khaled, S. K., et al. (2020) · Aging · doi:10.18632/aging.103605 · Cited by 17
“As epigenetic erasers, TET proteins oxidize 5mCs and initiate the first step of active DNA demethylation [30].”
BackgroundBrewitz, L., Tumber, A., Zhang, X., & Schofield, C. J. (2020) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2020.115675 · Cited by 17
Tsagaratou, A. (2021) · Immunological Reviews · doi:10.1111/imr.12940 · Cited by 16
Epigenetic Aspects and Prospects in Autoimmune Hepatitis
Czaja, A. J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.921765 · Cited by 17
Blanquart, C., Linot, C., Cartron, P., Tomaselli, D., Mai, A., & Bertrand, P. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867325666180706105903 · Cited by 17
TET2 catalyzes active DNA demethylation of the Sry promoter and enhances its expression
Okashita, N., Kuroki, S., Maeda, R., & Tachibana, M. (2019) · Scientific Reports · doi:10.1038/s41598-019-50058-7 · Cited by 13
Joshi, H. R., Hill, H. R., Zhou, Z., He, X., Voelkerding, K. V., & Kumánovics, A. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.1hi0120-169r · Cited by 14
DNA methylation in Hepatoblastoma-a literature review
Shen, G., Shen, H., Zhang, J., Yan, Q., & Liu, H. (2020) · The Italian Journal of Pediatrics/Italian journal of pediatrics · doi:10.1186/s13052-020-00877-6 · Cited by 16
“ment, TET enzymes are highly expressed and inhibit differentiation [83, 84].”
BackgroundYao, K., Liu, H., Yin, J., Yuan, J., & Tao, H. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02054-x · Cited by 16
“They showed reduced expression and impaired activity in a wide range of different cancer types [108].”
BackgroundEpigenetic Changes and Functions in Pneumoconiosis
Li, Y., Cheng, Z., Fan, H., Hao, C., & Yao, W. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/2523066 · Cited by 16
“…of DNA methylation gradually decreases with cell division and proliferation; and (2) active DNA demethylation, which is regulated mainly by deaminase activation-induced deaminase (AID)/ apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) and translocation t(10; 11) [18, 21 – 24].”
Iron: Not Just a Passive Bystander in AITD
Szklarz, M., Gontarz-Nowak, K., Matuszewski, W., & Bandurska-Stankiewicz, E. M. (2022) · Nutrients · doi:10.3390/nu14214682 · Cited by 18
Epigenetic Abnormalities in Chondrosarcoma
Bereza, M., Dembiński, M., Zając, A. E., Piątkowski, J., Dudzisz‐Śledź, M., Rutkowski, P. L., & Czarnecka, A. M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054539 · Cited by 18
“The TET enzymes work through the oxidation of 5-methylcytosines (5-mC), which results in a decrease in DNA methylation [39].”
BackgroundEpigenetic regulation of macrophage activation in chronic obstructive pulmonary disease
Zhang, F., Cui, Y., Zhang, T., & Yin, W. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1445372 · Cited by 17
“TET enzymes facilitate stepwise DNA demethylation (31), whereby TET1 decreases methylation at CpG promoter sites of STAT3, JAK1 and PIAS3, consequently elevates production of in fl ammatory cytokines and chemokines such as interleukin-8 (IL-8) which attracts neutrophils (32), and monocyte…”
BackgroundThe role of epigenetic modifications in Colorectal Cancer Metastasis
Su, R., Wu, X., Tao, L., & Wang, C. (2022) · Clinical & Experimental Metastasis · doi:10.1007/s10585-022-10163-w · Cited by 16
Histone Modifications and Their Targeting in Lymphoid Malignancies
Fernández-Serrano, M., Winkler, R., Santos, J. C., Pannérer, M.-M. L., Buschbeck, M., & Roué, G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010253 · Cited by 14
“Importantly, DNA methylation can only be indirectly removed by TET enzymes and subsequent DNA repair pathways or by dilution through cell divisions [37].”
Background
Metadata
- Authors
- Rasmussen, K. D., & Helin, K.
- Affiliations
- University of Copenhagen (DK)
- Corresponding author
- 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
- 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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