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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Figure 1. Domain structure of TET proteins. The C-terminal core catalytic domain shared by all TET enzymes consists of the DSBH domain, a cysteine-rich (Cys) domain, and binding sites for the Fe(II) and 2-OG cofactors. The DSBH domain contains a large low-complexity region of unknown function. TET1 and TET3 have an N-terminal CXXC domain that can bind directly to DNA and facilitate recruitment to genomic target sites.CC BY-NC · PubMed Central

Figure 2. Pathways of DNA demethylation mediated by TET enzymes. (A) Model of passive replication-dependent DNA demethylation. The diagrams illustrate the two opposite fates of a hemihydroxymethylated CpG dinucleotide through two rounds of DNA replication. The left panel shows the replication-dependent DNA demethylation, in which DNA methylation is lost on the DNA strand opposite to 5hmC. The right panel shows the reverse outcome, in which maintenance of DNA methylation is achieved by DNMT1 in complex with UHRF1/2 or DNMT3A/B. The relative extent of these two opposing outcomes of 5hmC deposition in vivo remains to be determined and is likely influenced by global as well as locus-specific factors. In both cases, newly replicated DNA dilutes 5hmC during cell division. (B) Model of active DNA demethylation by a TET/TDG (thymine–DNA–glycosylase)/BER (base excision repair)-dependent pathway. A cytosine base can be methylated by the DNA methylation machinery (DNMT1 or DNMT3A/B) to form 5mC, which in turn can be iteratively oxidized by TET enzymes to produce 5hmC, 5fC, and 5caC. TDG then recognizes 5fC and 5caC, and the oxidized cytosine base is excised. This yields an abasic site that is repaired by BER and results in restoration of the unmodified cytosine state. Additional pathways of active DNA demethylation have been suggested (for review, see Wu and Zhang 2014). (SAH) S-adenosyl-homocysteine; (SAM) S-adenosyl-methionine.CC BY-NC · PubMed Central

Figure 3. The dynamics of TET-mediated cytosine oxidation and its impact on DNA methylation patterns on regulatory elements in vivo. (A) Diagram illustrating the relative abundance of cytosines in the genome with “stable” levels of modifications as well as the small “transient” fractions that undergo rapid turnover and removal by active DNA demethylation processes. The stable levels of genomic 5caC have not been experimentally determined, as they are often under the detection limit. (B) Model illustrating the dual role of TET enzymes. The rate constant of TET enzymes to produce 5hmC from 5mC is fast, whereas the rate constants for further oxidation to 5fC and 5caC are considerably slower. On a majority of TET target sites, 5mC is oxidized and persists as “stable” 5hmC, likely due to low TET residence time (“stalling TET modification”). On a minority of sites, preferably located in open chromatin associated with regulatory elements, 5mC is oxidized iteratively to 5fC and 5caC and results in net DNA demethylation by the TET/TDG/BER pathway (“processive TET modification”). (C) Model illustrating the impact of loss of TET protein function on different regulatory elements. The protection of active and inactive CpG island promoters by the TET proteins is only one of several mechanisms by which they are protected against ectopic DNA methylation. In contrast, distal regulatory elements such as active enhancers are vulnerable to aberrant DNMT activity and become DNA hypermethylated upon loss of TET activity. (PcG) Polycomb group.CC BY-NC · PubMed Central

Figure 4. Illustration of the mutational landscape of TET2 in hematological diseases. A somatic mutation in TET2 results in premalignant hematopoiesis and clonal expansion. Additional oncogenic events cooperate with the initial TET2 mutation to drive the onset of a wide variety of hematopoietic malignancies. The frequencies of TET2 mutations in the different patient groups are indicated (for review, see Scourzic et al. 2015).CC BY-NC · PubMed Central

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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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“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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Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., He, C., & Zhang, Y. (2011) · Science · doi:10.1126/science.1210597 · Cited by 3,451 · cited 3×
“6-fold) substrates compared with the initial oxidation reaction of 5mC (Ito et al. 2011; Hu et al. 2015).”
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Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases
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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
Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation
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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…”
Background

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“As with other epigenetic modifications, DNA and histone methylation are both reversible and can be actively removed by TET enzymes and histone demethylases, respectively [46, 47].”
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“The loss of TET2 results in elevated H3K79 dimethylation, thereby leading to these cells being more reliant on DOT1L activity (55, 56).”
Low TET1 Expression Levels in COPD Are Associated with Airway and Blood NeutrophiliaPreprint
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Additional file 1 of MiR-183-5p promotes migration and invasion of prostate cancer by targeting TET1
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Additional file 1 of Targeted demethylation of the SLC5A7 promotor inhibits colorectal cancer progression
Li, Y., Liu, B., Yin, X., Jiang, Z., Fang, C., Chen, N., Zhang, B., Dai, L., & Yin, Y. (2022) · Figshare · doi:10.6084/m9.figshare.20347510
Additional file 2 of Identification of DNA methylation signatures associated with poor outcome in lower-risk Stage, Size, Grade and Necrosis (SSIGN) score clear cell renal cell cancer
Khoury, L. Y. E., Fu, S., Hlady, R. A., Wagner, R. T., Wang, L., Eckel-Passow, J. E., Castle, E. P., Stanton, M. L., Thompson, R. H., Parker, A. S., et al. (2021) · Figshare · doi:10.6084/m9.figshare.13605796
Additional file 1 of Epigenetic mechanisms underlying prostate cancer radioresistance
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Additional file 2 of Targeted demethylation of the SLC5A7 promotor inhibits colorectal cancer progression
Li, Y., Liu, B., Yin, X., Jiang, Z., Fang, C., Chen, N., Zhang, B., Dai, L., & Yin, Y. (2022) · Figshare · doi:10.6084/m9.figshare.20347516
Additional file 3 of Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers
Lemma, R. B., Fleischer, T., Martinsen, E., Ledsaak, M., Kristensen, V., Eskeland, R., Gabrielsen, O. S., & Mathelier, A. (2022) · Figshare · doi:10.6084/m9.figshare.19619310
Additional file 1 of Aberrant DNA hydroxymethylation reshapes transcription factor binding in myeloid neoplasms
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“TET2 is an α -ketoglutarate- and Fe 2+- dependent dioxygenase ( α -KGDDs) epigenetic enzyme maintaining DNA methylation by converting 5-methylcytosines (5mCs) to 5 hydroxymethylcytosine (5hmC)(Rasmussen and Helin, 2016).”
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“The activity of TET enzymes, which are involved in removing epigenetic marks and function as DNA demethylases, is an important tumor suppressor mechanism [183], and promoter methylation of some of the TET genes was associated with worse prognosis in OPC [184].”
Association of Baseline Neoplastic Microenvironment, Early Progression and Overall Survival in High-Risk Myelodysplastic Syndromes Treated with Azacytidine
Kupsa, T., Bělohlávková, P., Štajer, M., Knapova, E., Žák, P., & Horáček, J. M. (2026) · Bratislavské lekárske listy/Bratislava medical journal · doi:10.1007/s44411-026-00542-0
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“Coordinated alterations in demethylation dynamics have been deeply implicated in resurrecting silenced genes linked to stemness and therapeutic evasion [125].”
TET2 germline mutation in a patient with sequential lymphoid malignancies: a novel case report
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Christov, C. Z., Karabencheva‐Christova, T. G., Devadas, S., Bathir, J. S. R. S., Krishnan, A., & Thomas, M. G. (2026) · Encyclopedia of Inorganic and Bioinorganic Chemistry · doi:10.1002/9781119951438.eibc2895
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Bagacean, C. (2018) · theses.fr (ABES) · doi:10.70675/4409fbafz6d37z497cza3b9zf76d4e09d242
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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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