Alternative titles; symbols
HGNC Approved Gene Symbol: TET1
Cytogenetic location: 10q21.3 Genomic coordinates (GRCh38): 10:68,560,337-68,694,487 (from NCBI)
Methylation of DNA on cytosines is an important mechanism for silencing gene expression, and cytosine demethylation is required for gene activation. TET1 is the founding member of a family of methylcytosine dioxygenases that perform several steps required for cytosine demethylation and gene activation (Ito et al., 2011; He et al., 2011).
To identify the fusion partner of MLL in the translocation t(10;11)(q22;q23), Ono et al. (2002) analyzed leukemic cells from an individual with AML-M2 associated with t(10;11)(q22;q23), and identified TET1, which they called LCX (leukemia-associated protein with a CXXC domain), as a novel fusion partner of the MLL gene. Ono et al. (2002) found that the LCX gene encodes a 2,136-amino acid protein with a zinc-binding CXXC domain (which MLL also contains) within a methyltransferase domain, 3 nuclear localizations signals, and an alpha-helical coiled-coil region. Ono et al. (2002) found 3 RNA transcripts of LCX, each with a distinctive pattern of tissue expression. LCX was expressed in 8 of 22 leukemic cell lines, but not in EBV-induced normal B-cell lines. The MLL-LCX fusion protein lacked a CXXC domain of LCX, but retained an alpha-helical coiled-coil region at the C terminus, similar to MLL-AF6 (see 159559), MLL-AF1P (see 600051), and other fusion proteins involved in the pathogenesis of 11q23-associated leukemia.
In a computational search for enzymes that could modify 5-methylcytosine (5mC), Tahiliani et al. (2009) identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. They showed that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference-mediated depletion of TET1. Thus, Tahiliani et al. (2009) concluded that TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.
Ito et al. (2010) extended the study of Tahiliani et al. (2009) by demonstrating that all 3 mouse TET proteins, Tet1, Tet2 (612839), and Tet3 (613555), can catalyze the conversion of 5mC to 5hmC. Tet1 has an important role in mouse embryonic stem cell maintenance through maintaining the expression of Nanog (607937) in embryonic stem cells. Downregulation of Nanog via Tet1 knockdown correlated with methylation of the Nanog promoter, supporting a role for Tet1 in regulating DNA methylation status. Furthermore, knockdown of Tet1 in preimplantation embryos resulted in a bias towards trophectoderm differentiation. Thus, Ito et al. (2010) concluded that their studies not only uncovered the enzymatic activity of the Tet proteins, but also demonstrated a role for Tet1 in embryonic stem cell maintenance and inner cell mass cell specification.
Williams et al. (2011) showed that TET1 binds throughout the genome of embryonic stem cells, with the majority of binding sites located at transcription start sites of CpG-rich promoters and within genes. The hmC modification is found in gene bodies and in contrast to mC is also enriched at CpG-rich transcription start sites. Williams et al. (2011) provided further evidence that TET1 has a role in transcriptional repression. TET1 binds a significant proportion of Polycomb group target genes. Furthermore, TET1 associates and colocalizes with the SIN3A (607776) corepressor complex. Williams et al. (2011) proposed that TET1 fine tunes transcription, opposes aberrant DNA methylation at CpG-rich sequences, and thereby contributes to the regulation of DNA methylation fidelity.
Using chromatin immunoprecipitation coupled with high-throughput DNA sequencing, Wu et al. (2011) demonstrated in mouse embryonic stem (ES) cells that Tet1 is preferentially bound to CpG-rich sequences at promoters of both transcriptionally active and Polycomb-repressed genes. Despite an increase in levels of DNA methylation at many Tet1-binding sites, Tet1 depletion does not lead to downregulation of all the Tet1 targets. Interestingly, although Tet1-mediated promoter hypomethylation is required for maintaining the expression of a group of transcriptionally active genes, it is also involved in repression of Polycomb-targeted developmental regulators. Tet1 contributes to silencing of this group of genes by facilitating recruitment of Polycomb repressive complex-2 (PRC2; see 601573) to CpG-rich gene promoters. Thus, Wu et al. (2011) concluded that their study not only establishes a role for Tet1 in modulating DNA methylation levels at CpG-rich promoters, but also reveals a dual function of Tet1 in promoting transcription of pluripotency factors as well as participating in the repression of Polycomb-targeted developmental regulators.
Pastor et al. (2011) described 2 novel and specific approaches to profile the genomic localization of 5hmC. The first approach, which they called GLIB (glucosylation, periodate oxidation, biotinylation), uses a combination of enzymatic and chemical steps to isolate DNA fragments containing as few as a single 5hmC. The second approach involves conversion of 5hmC to cytosine 5-methylenesulfonate (CMS) by treatment of genomic DNA with sodium bisulfite, followed by immunoprecipitation of CMS-containing DNA with a specific antiserum to CMS. High-throughout sequencing of 5hmC-containing DNA from mouse embryonic stem cells showed strong enrichment within exons and near transcriptional start sites. 5hmC was especially enriched at the start sites of genes whose promoters bear dual histone-3 lysine-27 trimethylation (H3K27me3) and histone-3 lysine-4 trimethylation (H3K4me3) marks. Pastor et al. (2011) concluded that 5hmC has a probable role in transcriptional regulation, and suggested a model in which 5hmC contributes to the 'poised' chromatin signature found at developmentally-regulated genes in embryonic stem cells.
Ficz et al. (2011) used antibodies against 5hmC and 5mC together with high-throughput sequencing to determine genomewide patterns of methylation and hydroxymethylation in mouse wildtype and mutant ES cells and differentiating embryoid bodies. They found that 5hmC is mostly associated with euchromatin and that whereas 5mC is underrepresented at gene promoters and CpG islands, 5hmC is enriched and is associated with increased transcriptional levels. Most, if not all, 5hmC in the genome depends on preexisting 5mC and the balance between these 2 modifications is different between genomic regions. Knockdown of Tet1 and Tet2 causes downregulation of a group of genes that includes pluripotency-related genes (Esrrb, 602167; Prdm14, 611781; Dppa3, 608408; Klf2, 602016; Tcl1, 186960; and Zfp42) and a concomitant increase in methylation of their promoters, together with an increased propensity of ES cells for extraembryonic lineage differentiation. Declining levels of TETs during differentiation are associated with decreased hydroxymethylation levels at the promoters of ES cell-specific genes together with increased methylation and gene silencing. Ficz et al. (2011) proposed that the balance between hydroxymethylation and methylation in the genome is inextricably linked with the balance between pluripotency and lineage commitment.
Ito et al. (2011) showed that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity-dependent manner. Furthermore, Ito et al. (2011) revealed the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, Ito et al. (2011) concluded that they identified 2 previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins, and raised the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.
He et al. (2011) demonstrated that 5mC and 5hmC in DNA are oxidized to 5caC by Tet dioxygenases in vitro and in cultured cells. 5caC is specifically recognized and excised by thymine-DNA glycosylase (TDG; 601423). Depletion of TDG in mouse embryonic stem cells leads to accumulation of 5caC to a readily detectable level. He et al. (2011) concluded that oxidation of 5mC by Tet proteins followed by TDG-mediated base excision of 5caC constitutes a pathway for active DNA demethylation.
Guo et al. (2011) found that transfection of HEK293 cells with TET1 induced DNA replication-independent demethylation of 5hmC in the context of both CpG and non-CpG DNA. Pharmacologic inhibition of the base excision repair enzymes PARP (see 173870) or APE1 (APEX1; 107748) reduced demethylation of 5hmC DNA. Expression of the cytidine deaminase AID (AICDA; 605257) or of the APOBEC cytidine deaminases mouse Apobec1 (600130) or human APOBEC2 (604797), APOBEC3A (607109), APOBEC3C (607750), or APOBEC3E (APOBEC3D; 609900), but not APOBEC3B (607110) or APOBEC3G (607113), significantly increased demethylation of 5hmC DNA. Overexpression of TET1 or AID in adult mouse dentate gyrus via adenovirus-mediated gene transfer increased and decreased 5hmC levels, respectively, and resulted in upregulated expression of brain-specific variants of Bdnf (113505) and Fgf1 (131220). Knockdown of endogenous Tet1 or Apobec1 expression in adult dentate gyrus abolished stimulation-induced demethylation of brain-specific Bdnf and Fgf1 promoters. Guo et al. (2011) concluded that TET1, AID, and APOBEC cooperate in a base excision-mediated pathway of active DNA demethylation.
Using a loss-of-function approach in mice, Yamaguchi et al. (2012) showed that the 5mC-specific dioxygenase Tet1 has an important role in regulating meiosis in mouse oocytes. Tet1 deficiency significantly reduced female germ cell numbers and fertility. Univalent chromosomes and unresolved DNA double-strand breaks were also observed in Tet1-deficient oocytes. Tet1 deficiency does not greatly affect the genomewide demethylation that takes place in primordial germ cells, but leads to defective DNA demethylation and decreased expression of a subset of meiotic genes. Yamaguchi et al. (2012) concluded that their study established a function for Tet1 in meiosis and meiotic gene activation in female germ cells.
Mouse primordial germ cells (PGCs) undergo sequential epigenetic changes and genomewide DNA demethylation to reset the epigenome for totipotency. Hackett et al. (2013) demonstrated that erasure of CpG methylation in PGCs occurs via conversion to 5hmC, driven by high levels of Tet1 and Tet2 (612839). Global conversion to 5hmC initiates asynchronously among PGCs at embryonic day (E) 9.5 to E10.5 and accounts for the unique process of imprint erasure. Mechanistically, 5hmC enrichment is followed by its protracted decline thereafter at a rate consistent with replication-coupled dilution. The conversion to 5hmC is an important component of parallel redundant systems that drive comprehensive reprogramming in PGCs. Nonetheless, Hackett et al. (2013) identified rare regulatory elements that escape systematic DNA demethylation in PGCs, providing a potential mechanistic basis for transgenerational epigenetic inheritance.
Using enhanced purification techniques and a stringent computational algorithm, Costa et al. (2013) identified 27 high-confidence protein interaction partners of Nanog (607937) in mouse embryonic stem cells. These consisted of 19 partners of Nanog, including the ten-eleven translocation (TET) family methylcytosine hydroxylase Tet1. Costa et al. (2013) confirmed physical association of Nanog with Tet1, and demonstrated that Tet1, in synergy with Nanog, enhanced the efficiency of reprogramming. Costa et al. (2013) also found physical association and reprogramming synergy of Tet2 with Nanog, and demonstrated that knockdown of Tet2 abolished the reprogramming synergy of Nanog with a catalytically deficient mutant of Tet1. These results indicated that the physical interaction between Nanog and Tet1/Tet2 proteins facilitates reprogramming in a manner that is dependent on the catalytic activity of Tet1/Tet2. Tet1 and Nanog cooccupy genomic loci of genes associated with both maintenance of pluripotency and lineage commitment in embryonic stem cells, and Tet1 binding is reduced upon Nanog depletion. Coexpression of Nanog and Tet1 increased 5-hydroxymethylcytosine levels at the top-ranked common target loci Esrrb (602167) and Oct4 (164177), resulting in priming of their expression before reprogramming to naive pluripotency. Costa et al. (2013) proposed that TET1 is recruited by NANOG to enhance the expression of a subset of key reprogramming target genes.
Blaschke et al. (2013) reported that addition of vitamin C to mouse embryonic stem cells promotes Tet activity, leading to a rapid and global increase in 5hmC. This is followed by DNA demethylation of many gene promoters and upregulation of demethylated germline genes. Tet1 binding is enriched near the transcription start site of genes affected by vitamin C treatment. Importantly, vitamin C, but not other antioxidants, enhances the activity of recombinant Tet1 in a biochemical assay, and the vitamin C-induced changes in 5hmC and 5mC are entirely suppressed in Tet1 and Tet2 (612839) double-knockout embryonic stem cells. Vitamin C has a stronger effect on regions that gain methylation in cultured embryonic stem cells compared to blastocysts, and in vivo are methylated only after implantation. In contrast, imprinted regions and intracisternal A particle retroelements, which are resistant to demethylation in the early embryo, are resistant to vitamin C-induced DNA demethylation. Blaschke et al. (2013) concluded that the results of this study established vitamin C as a direct regulator of Tet activity and DNA methylation fidelity in embryonic stem cells.
Chen et al. (2013) reported that TET1 either positively or negatively regulates somatic cell reprogramming depending on the absence or presence of vitamin C. TET1 deficiency enhances reprogramming, and its overexpression impairs reprogramming in the context of vitamin C by modulating the obligatory mesenchymal-to-epithelial transition. In the absence of vitamin C, TET1 promotes somatic cell reprogramming independent of mesenchymal-to-epithelial transition. TET1 consistently regulates 5hmC formation at loci critical for mesenchymal-to-epithelial transition in a vitamin C-dependent fashion. Chen et al. (2013) concluded that their findings suggested that vitamin C has a vital role in determining the biologic outcome of TET1 function at the cellular level.
Yamaguchi et al. (2013) reported that TET1 has a critical role in the erasure of genomic imprinting. They found that despite their identical genotype, progeny derived from mating between Tet1 knockout males and wildtype females exhibit a number of variable phenotypes including placental, fetal, and postnatal growth defects, and early embryonic lethality. These defects are, at least in part, caused by the dysregulation of imprinted genes, such as Peg10 (609810) and Peg3 (601483), which exhibit aberrant hypermethylation in the paternal allele of differential methylated regions (DMRs). RNA sequencing revealed extensive dysregulation of imprinted genes in the next generation due to paternal loss of Tet1 function. Genomewide DNA methylation analysis of embryonic day 13.5 primordial germ cells and sperm of Tet1 knockout mice revealed hypermethylation of DMRs of imprinted genes in sperm, which can be traced back to primordial germ cells. Analysis of the DNA methylation dynamics in reprogramming primordial germ cells indicated that TET1 functions to wipe out remaining methylation, including imprinted genes, at the late reprogramming stage. Furthermore, Yamaguchi et al. (2013) provided evidence supporting the role of TET1 in the erasure of paternal imprints in the female germline.
Thienpont et al. (2016) demonstrated that the activity of oxygen-dependent ten-eleven translocation (TET) enzymes is reduced by tumor hypoxia in human and mouse cells. TET enzymes catalyze DNA demethylation through 5-methylcytosine oxidation. This reduction in activity occurs independently of hypoxia-associated alterations in TET expression, proliferation, metabolism, hypoxia-inducible factor (HIF; see 603348) activity or reactive oxygen species, and depends directly on oxygen shortage. Hypoxia-induced loss of TET activity increases hypermethylation at gene promoters in vitro. In patients, tumor suppressor gene promoters are markedly more methylated in hypoxic tumor tissue, independent of proliferation, stromal cell infiltration, or tumor characteristics. Thienpont et al. (2016) suggested that up to half of hypermethylation events are due to hypoxia, with these events conferring a selective advantage. Accordingly, increased hypoxia in mouse breast tumors increases hypermethylation, while restoration of tumor oxygenation abrogates this effect. Tumor hypoxia therefore acts as a novel regulator of DNA methylation.
In mice, germ cells are first specified in the developing embryo around embryonic day (E)6.25 as primordial germ cells (PGCs). Following subsequent migration into the developing gonad, PGCs undergo a wave of extensive epigenetic reprogramming around E10.5-E11.5, including genomewide loss of 5-methylcytosine. Using an integrative approach, Hill et al. (2018) demonstrated that this complex reprogramming process involves coordinated interplay among promoter sequence characteristics, DNA (de)methylation, the polycomb (PRC1) complex (see 600346), and both DNA demethylation-dependent and -independent functions of TET1 to enable the activation of a critical set of germline reprogramming-responsive genes involved in gamete generation and meiosis. Hill et al. (2018) concluded that these studies revealed an unexpected role for TET1 in maintaining but not driving DNA demethylation in gonadal PGCs.
Ono et al. (2002) found that the TET1 gene contains at least 12 exons.
By sequence analysis of a mapped BAC clone and by FISH, Ono et al. (2002) mapped the TET1 gene to chromosome 10q22.
Exclusion Studies
Abdel-Wahab et al. (2009) did not find somatic mutations in the TET1 gene among 96 patients with myeloproliferative neoplasms.
Khoueiry et al. (2017) found that knockout of Tet1 expression in mice caused defects at late gastrulation. Contrary to expectations, Tet1 knockout caused both aberrant down- and upregulation of gene expression, which was due to defects in both enzymatic methylation and nonenzymatic nonmethylation events. The nonenzymatic consequence of Tet1 knockout appeared to be mediated by its noncatalytic N-terminal domain. In extraembryonic ectoderm, Tet1 suppressed expression of metabolic genes, coincident with a metabolic shift from glycolysis to oxidative respiration with differentiation in epiblast cells. Tet1 knockout also influenced telomere stability at the epiblast stage.
Dai et al. (2016) demonstrated that inactivation of all 3 Tet genes in mice leads to gastrulation phenotypes, including primitive streak patterning defects in association with impaired maturation of axial mesoderm and failed specification of paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal (601265) signaling. Introduction of a single mutant allele of Nodal in the Tet mutant background partially restored patterning, suggesting that hyperactive Nodal signaling contributes to the gastrulation failure of Tet mutants. Increased Nodal signaling is probably due to diminished expression of the Lefty1 (603037) and Lefty2 (601877) genes, which encode inhibitors of Nodal signaling. Moreover, reduction in Lefty gene expression is linked to elevated DNA methylation, as both Lefty-Nodal signaling and normal morphogenesis are largely restored in Tet-deficient embryos when the Dnmt3a (602769) and Dnmt3b (602900) genes are disrupted. Additionally, a point mutation in Tet that specifically abolishes the dioxygenase activity causes similar morphologic and molecular abnormalities as the null mutation. Dai et al. (2016) concluded that TET-mediated oxidation of 5-methylcytosine modulates Lefty-Nodal signaling by promoting demethylation in opposition to methylation by DNMT3A and DNMT3B. The authors also concluded that their findings revealed a fundamental epigenetic mechanism featuring dynamic DNA methylation and demethylation crucial to regulation of key signaling pathways in early body plan formation.
DiTroia et al. (2019) showed that maternal vitamin C is required for proper DNA demethylation and the development of female fetal germ cells in a mouse model. Maternal vitamin C deficiency (see 240400) did not affect overall embryonic development but led to reduced numbers of germ cells, delayed meiosis, and reduced fecundity in adult offspring. The transcriptome of germ cells from vitamin-C-deficient embryos was remarkably similar to that of embryos carrying a null mutation in Tet1. Vitamin C deficiency led to an aberrant DNA methylation profile that included incomplete demethylation of key regulators of meiosis and transposable elements. DiTroia et al. (2019) concluded that their findings revealed that deficiency in vitamin C during gestation partially recapitulates loss of TET1, and provided a potential intergenerational mechanism for adjusting fecundity to environmental conditions.
Abdel-Wahab, O., Mullally, A., Hedvat, C., Garcia-Manero, G., Patel, J., Wadleigh, M., Malinge, S., Yao, J., Kilpivaara, O., Bhat, R., Huberman, K., Thomas, S., and 12 others. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 114: 144-147, 2009. [PubMed: 19420352] [Full Text: https://doi.org/10.1182/blood-2009-03-210039]
Blaschke, K., Ebata, K. T., Karimi, M. M., Zepeda-Martinez, J. A., Goyal, P., Mahapatra, S., Tam, A., Laird, D. J., Hirst, M., Rao, A., Lorincz, M. C., Ramalho-Santos, M. Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500: 222-226, 2013. [PubMed: 23812591] [Full Text: https://doi.org/10.1038/nature12362]
Chen, J., Guo, L., Zhang, L., Wu, H., Yang, J., Liu, H., Wang, X., Hu, X., Gu, T., Zhou, Z., Liu, J., Liu, J., and 10 others. Vitamin C modulates TET1 function during somatic cell reprogramming. Nature Genet. 45: 1504-1509, 2013. [PubMed: 24162740] [Full Text: https://doi.org/10.1038/ng.2807]
Costa, Y., Ding, J., Theunissen, T. W., Faiola, F., Hore, T. A., Shliaha, P. V., Fidalgo, M., Saunders, A., Lawrence, M., Dietmann, S., Das, S., Levasseur, D. N., Li, Z., Xu, M., Reik, W., Silva, J. C. R., Wang, J. NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495: 370-374, 2013. [PubMed: 23395962] [Full Text: https://doi.org/10.1038/nature11925]
Dai, H.-Q., Wang, B.-A., Yang, L., Chen, J.-J., Zhu, G.-C., Sun, M.-L., Ge, H., Wang, R., Chapman, D. L., Tang, F., Sun, X., Xu, G.-L. TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling. Nature 538: 528-532, 2016. [PubMed: 27760115] [Full Text: https://doi.org/10.1038/nature20095]
DiTroia, S. P., Percharde, M., Guerquin, M.-J., Wall, E., Collignon, E., Ebata, K. T., Mesh, K., Mahesula, S., Agathocleous, M., Laird, D. J., Livera, G., Ramalho-Santos, M. Maternal vitamin C regulates reprogramming of DNA methylation and germline development. Nature 573: 271-275, 2019. Note: Erratum: Nature 576: E1, 2019. [PubMed: 31485074] [Full Text: https://doi.org/10.1038/s41586-019-1536-1]
Ficz, G., Branco, M. R., Seisenberger, S., Santos, F., Krueger, F., Hore, T. A., Marques, C. J., Andrews, S., Reik, W. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature 473: 398-402, 2011. [PubMed: 21460836] [Full Text: https://doi.org/10.1038/nature10008]
Guo, J. U., Su, Y., Zhong, C., Ming, G.-I., Song, H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145: 423-434, 2011. [PubMed: 21496894] [Full Text: https://doi.org/10.1016/j.cell.2011.03.022]
Hackett, J. A., Sengupta, R., Zylicz, J. J., Murakami, K., Lee, C., Down, T. A., Surani, M. A. Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339: 448-452, 2013. [PubMed: 23223451] [Full Text: https://doi.org/10.1126/science.1229277]
He, Y.-F., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., Sun, Y., Li, X., Dai, Q., Song, C.-X., Zhang, K., He, C., Xu, G.-L. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333: 1303-1307, 2011. [PubMed: 21817016] [Full Text: https://doi.org/10.1126/science.1210944]
Hill, P. W. S., Leitch, H. G., Requena, C. E., Sun, Z., Amouroux, R., Roman-Trufero, M., Borkowska, M., Terragni, J., Vaisvila, R., Linnett, S., Bagci, H., Dharmalingham, G., Haberle, V., Lenhard, B., Zheng, Y., Pradhan, S., Hajkova, P. Epigenetic reprogramming enables the transition from primordial germ cell to gonocyte. Nature 555: 392-396, 2018. [PubMed: 29513657] [Full Text: https://doi.org/10.1038/nature25964]
Ito, S., D'Alessio, A. C., Taranova, O. V., Hong, K., Sowers, L. C., Zhang, Y. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466: 1129-1133, 2010. [PubMed: 20639862] [Full Text: https://doi.org/10.1038/nature09303]
Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., He, C., Zhang, Y. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333: 1300-1303, 2011. [PubMed: 21778364] [Full Text: https://doi.org/10.1126/science.1210597]
Khoueiry, R., Sohni, A., Thienpont, B., Luo, X., Vande Velde, J., Bartoccetti, M., Boeckx, B., Zwijsen, A., Rao, A., Lambrechts, D., Koh, K. P. Lineage-specific functions of TET1 in the postimplantation mouse embryo. Nature Genet. 49: 1061-1072, 2017. [PubMed: 28504700] [Full Text: https://doi.org/10.1038/ng.3868]
Ono, R., Taki, T., Taketani, T., Taniwaki, M., Kobayashi, H., Hayashi, Y. 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 Res. 62: 4075-4080, 2002. [PubMed: 12124344]
Pastor, W. A., Pape, U. J., Huang, Y., Henderson, H. R., Lister, R., Ko, M., McLoughlin, E. M., Brudno, Y., Mahapatra, S., Kapranov, P., Tahiliani, M., Daley, G. Q., Liu, X. S., Ecker, J. R., Milos, P. M., Agarwal, S., Rao, A. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 473: 394-397, 2011. [PubMed: 21552279] [Full Text: https://doi.org/10.1038/nature10102]
Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L. M., Liu, D. R., Aravind, L., Rao, A. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324: 930-935, 2009. [PubMed: 19372391] [Full Text: https://doi.org/10.1126/science.1170116]
Thienpont, B., Steinbacher, J., Zhao, H., D'Anna, F., Kuchnio, A., Ploumakis, A., Ghesquiere, B., Van Dyck, L., Boeckx, B., Schoonjans, L., Hermans, E., Amant, F., Kristensen, V. N., Koh, K. P., Mazzone, M., Coleman, M. L., Carell, T., Carmeliet, P., Lambrechts, D. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature 537: 63-68, 2016. [PubMed: 27533040] [Full Text: https://doi.org/10.1038/nature19081]
Williams, K., Christensen, J., Pedersen, M. T., Johansen, J. V., Cloos, P. A. C., Rappsilber, J., Helin, K. TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity. Nature 473: 343-348, 2011. [PubMed: 21490601] [Full Text: https://doi.org/10.1038/nature10066]
Wu, H., D'Alessio, A. C., Ito, S., Xia, K., Wang, Z., Cui, K., Zhao, K., Sun, Y. E., Zhang, Y. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473: 389-393, 2011. [PubMed: 21451524] [Full Text: https://doi.org/10.1038/nature09934]
Yamaguchi, S., Hong, K., Liu, R., Shen, L., Inoue, A., Diep, D., Zhang, K., Zhang, Y. Tet1 controls meiosis by regulating meiotic gene expression. Nature 492: 443-447, 2012. [PubMed: 23151479] [Full Text: https://doi.org/10.1038/nature11709]
Yamaguchi, S., Shen, L., Liu, Y., Sendler, D., Zhang, Y. Role of Tet1 in erasure of genomic imprinting. Nature 504: 460-464, 2013. [PubMed: 24291790] [Full Text: https://doi.org/10.1038/nature12805]