Affinage

TET3

Methylcytosine dioxygenase TET3 · UniProt O43151

Length
1795 aa
Mass
193.7 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TET3 is an α-ketoglutarate–dependent methylcytosine dioxygenase that oxidizes 5-methylcytosine to 5-hydroxymethylcytosine to drive locus-specific and genome-wide DNA demethylation across development, the nervous system, and metabolic tissues (PMID:21892189, PMID:23217707). In the mouse zygote it is the predominant TET enzyme, enriched in the male pronucleus and oxidizing both paternal and (less prominently) maternal genomes, with demethylation achieved largely by coupling 5mC oxidation to replication-dependent dilution while also protecting certain CpG islands from methylation buildup (PMID:21892189, PMID:25280220, PMID:26507142, PMID:25497087); this oocyte-derived activity is required for correct imprinting and for postnatal metabolic health, as TET3 deficiency causes persistent hypermethylation of insulin-secretion genes in offspring (PMID:35585240). Genomic targeting is mediated by an intrinsic N-terminal CXXC domain present in the full-length isoform that binds unmethylated CpG and has highest affinity for 5-carboxylcytosine, positioning TET3 at transcription start sites (PMID:23217707, PMID:26774490, PMID:23690950). Catalytic activity is governed by interacting partners and post-translational modification: PGC7/Stella suppresses TET3 to protect imprints (PMID:24322296), CDK5 phosphorylates the catalytic domain to retune its activity during neuronal differentiation (PMID:31807777), SUMO1 stabilizes the protein (PMID:37244630), and a nuclear-redirected glutamate dehydrogenase supplies α-ketoglutarate on-site to fuel demethylation in activated neurons (PMID:34215750). Beyond catalysis, TET3 functions as a chromatin scaffold—recruiting and stabilizing OGT to promote HCF1 GlcNAcylation and SET1/COMPASS-dependent H3K4me3 (PMID:24304661, PMID:23353889), engaging HDAC1/SIN3A to repress IFN-β independently of demethylation (PMID:27425624), and stabilizing thyroid hormone receptors on chromatin (PMID:28716910). In neurons TET3 acts as a synaptic-activity sensor coupling 5mC oxidation and base-excision repair to surface GluR1 levels and homeostatic plasticity (PMID:25915473), and it is recruited to DNA double-strand breaks to favor homologous recombination repair (PMID:39192299, PMID:28325772). In metabolic and fibrotic disease it both activates and represses gene programs in a context-specific manner, restricting feeding via the Agrp promoter in AGRP neurons (PMID:36189793), destabilizing PGC-1α to promote muscle insulin resistance (PMID:38216792), and driving adipogenesis through C/EBPδ-directed demethylation (PMID:35788760). Catalytic-domain missense variants cause a Mendelian neurodevelopmental disorder (TET3 deficiency/Beck-Fahrner syndrome) marked by a genome-wide hypermethylation episignature (PMID:31928709, PMID:34750377).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2011 High

    Established that TET3 is the enzyme responsible for active oxidative reprogramming of the paternal genome at fertilization, answering how zygotic DNA demethylation is initiated.

    Evidence Conditional KO mice with immunofluorescence for pronuclear localization and 5mC/5hmC staining in Tet3-deficient zygotes

    PMID:21892189

    Open questions at the time
    • Did not resolve genome-wide vs locus-specific demethylation contribution
    • Mechanism of pronuclear targeting unaddressed
  2. 2012 High

    Defined the structural and functional logic of TET3 targeting and catalysis, showing both the CXXC domain and dioxygenase activity are required for developmental gene regulation.

    Evidence CXXC domain structural/biochemical studies plus Xenopus loss-of-function and domain-deletion mutants with promoter 5mC/5hmC readouts

    PMID:23217707

    Open questions at the time
    • Mammalian CXXC isoform usage not fully resolved here
    • Direct genomic binding map absent
  3. 2013 High

    Revealed a non-catalytic scaffolding axis whereby TET3 binds and stabilizes OGT on chromatin to drive HCF1 GlcNAcylation and SET1/COMPASS-dependent H3K4me3.

    Evidence Affinity purification/MS, reciprocal Co-IP with deletion mapping, ChIP co-localization, GlcNAcylation and COMPASS integrity assays

    PMID:23353889 PMID:24304661

    Open questions at the time
    • Whether this axis operates in zygotic reprogramming untested
    • Direct chromatin recruitment determinants unclear
  4. 2013 High

    Showed TET3 activity is negatively regulated by PGC7/Stella, explaining how imprinted loci escape oxidative demethylation.

    Evidence In vitro binding, Co-IP, enzymatic suppression assays and methylation analysis at imprinting loci

    PMID:24322296

    Open questions at the time
    • Stoichiometry and structural basis of inhibition unknown
    • Single lab
  5. 2014 High

    Resolved the mechanism of zygotic demethylation, showing TET3 acts largely by coupling to DNA replication while also protecting CpG islands and remodeling gene bodies linked to genome activation.

    Evidence Genome-scale bisulfite sequencing of Tet3-depleted and replication-inhibited zygotes with allele resolution

    PMID:25280220 PMID:25497087

    Open questions at the time
    • Relative weighting of active vs passive demethylation per locus class incomplete
    • Mechanism of CpG-island protection unexplained
  6. 2015 High

    Demonstrated that the maternal Tet3 knockout developmental phenotype reflects haploinsufficiency rather than failed paternal 5mC oxidation, separating gene dosage from catalytic reprogramming.

    Evidence Genetic rescue with paternal pronucleus reconstruction and genome-scale methylation analysis across crosses

    PMID:25640176

    Open questions at the time
    • Which dosage-sensitive TET3 functions cause sublethality unidentified
  7. 2015 High

    Identified TET3 as a synaptic-activity sensor controlling excitatory transmission through 5mC oxidation, base-excision repair, and surface GluR1 regulation.

    Evidence Bidirectional shRNA knockdown/overexpression with electrophysiology, surface receptor quantification and BER inhibition in hippocampal neurons

    PMID:25915473

    Open questions at the time
    • Direct genomic targets controlling GluR1 not mapped
    • Link between BER and receptor trafficking mechanistically incomplete
  8. 2016 High

    Provided the structural basis for TET3 isoform-specific targeting, showing the full-length CXXC domain preferentially recognizes 5-carboxylcytosine and positions TET3 at transcription start sites.

    Evidence Crystal structure of CXXC bound to 5caC-DNA, in vitro binding by modification state, and neuronal ChIP-seq

    PMID:26774490

    Open questions at the time
    • Functional consequence of 5caC preference in vivo unclear
    • Isoform-specific targeting in non-neuronal cells untested
  9. 2016 Medium

    Established a demethylation-independent immunoregulatory function in which TET3's catalytic domain recruits HDAC1/SIN3A to repress IFN-β.

    Evidence Catalytic-dead mutant rescue, Co-IP of HDAC1/SIN3A and ChIP at the Ifnb1 promoter

    PMID:27425624

    Open questions at the time
    • Single lab
    • How catalytic domain selects the Ifnb1 locus unknown
  10. 2017 Medium

    Connected TET3 to the DNA damage response by showing it is an ATR substrate whose 5mC oxidation supports efficient repair.

    Evidence ATR kinase assay with TET3 as substrate plus expression modulation and repair/cell-death assays

    PMID:28325772

    Open questions at the time
    • Phosphosites and their functional effect not mapped
    • Direct recruitment to lesions not shown here
  11. 2017 Medium

    Defined a non-catalytic transcriptional co-regulator role in which TET3 stabilizes thyroid hormone and other nuclear receptors on chromatin.

    Evidence Co-IP, ChIP for receptor chromatin retention, reporter assays and catalytic-dead mutant retaining interaction

    PMID:28716910

    Open questions at the time
    • Single lab
    • Generality across nuclear receptor superfamily incompletely defined
  12. 2019 Medium

    Showed non-catalytic, allele-specific TET3 binding maintains neural stem cell identity by repressing the imprinted Snrpn-BMP2 axis and preventing premature astrocytic differentiation.

    Evidence Conditional KO and inducible knockdown in NSCs/NPCs with allele-specific binding, methylation profiling and BMP2 rescue

    PMID:30979904 PMID:31646359

    Open questions at the time
    • Single lab
    • Mechanism of allele-specific recognition unresolved
  13. 2020 High

    Identified CDK5 phosphorylation of the TET3 catalytic domain as a switch that retunes dioxygenase activity, H2A.Z association and neuronal gene activation.

    Evidence In vitro CDK5 kinase assay, phospho-mutant expression in triple-KO ESCs, 5hmC mapping and H2A.Z ChIP during differentiation

    PMID:31807777

    Open questions at the time
    • In vivo relevance of phosphosites untested
    • How phosphorylation alters H2A.Z binding mechanistically unclear
  14. 2020 Medium

    Established TET3 as a causal gene for a Mendelian neurodevelopmental disorder, linking catalytic loss-of-function to human disease and behavior.

    Evidence Patient missense variant identification with catalytic activity assays, clinical phenotyping and adult-neuron conditional KO behavioral/transcriptomic analysis

    PMID:31928709 PMID:32103150

    Open questions at the time
    • Single clinical cohort
    • Molecular targets driving behavioral phenotypes not defined
  15. 2021 Medium

    Explained how neurons supply cofactor for TET3, showing glutamate dehydrogenase is redirected to the nucleus to generate α-ketoglutarate on-site and stimulate TET3 activity upon neuronal activation.

    Evidence Co-IP, subcellular fractionation, nuclear αKG measurement and TET3 activity assays with/without GDH

    PMID:34215750

    Open questions at the time
    • Single lab
    • Mechanism of GDH nuclear redirection unresolved
  16. 2021 Medium

    Provided a clinical functional biomarker by defining a genome-wide hypermethylation episignature for TET3 catalytic loss-of-function in patient blood.

    Evidence Genome-wide methylation array profiling of TET3-deficient patients with validation against other disorders

    PMID:34750377

    Open questions at the time
    • Single study
    • Tissue-specificity of the episignature not established
  17. 2022 High

    Linked maternal TET3 dosage to offspring metabolic disease, showing reduced oocyte TET3 in hyperglycemia causes persistent hypermethylation of insulin-secretion genes correctable by Tet3 mRNA.

    Evidence Hyperglycemia model, oocyte conditional KO, developmental bisulfite sequencing, insulin secretion assays and mRNA rescue

    PMID:35585240

    Open questions at the time
    • Human translation limited to expression correlation
    • Other affected loci beyond Gck incompletely cataloged
  18. 2022 High

    Defined adult tissue-specific TET3 functions in energy balance and metabolism: leptin-driven repression of Agrp in AGRP neurons, destabilization of PGC-1α in muscle, and C/EBPδ-directed demethylation in adipogenesis.

    Evidence Cell-type-specific KO/CRISPR, ChIP and 5hmC at target promoters, Co-IP of TET3 with C/EBPδ and PGC-1α, WGBS and metabolic phenotyping

    PMID:35788760 PMID:36189793 PMID:38216792

    Open questions at the time
    • Whether these roles share a common recruitment logic unclear
    • Reconciling activating vs repressive outcomes mechanistically incomplete
  19. 2024 Medium

    Implicated TET3 in DNA double-strand break repair pathway choice, showing recruitment to breaks promotes homologous recombination and restrains fibroblast proliferation.

    Evidence TET3 recruitment to H2O2-induced DSBs, HR/NHEJ pathway assays and KO/overexpression in cardiac fibrosis models

    PMID:39192299

    Open questions at the time
    • Single lab
    • Whether recruitment is catalytic or scaffolding not resolved
  20. 2024 Medium

    Dissected catalytic versus non-catalytic TET3 functions in lineage specification, showing catalytic activity activates neural genes while non-catalytic roles suppress mesoderm and regulate Dnmt1.

    Evidence Catalytic-mutant vs full-knockout ESC differentiation with WGBS and RNA-seq

    PMID:38580843

    Open questions at the time
    • Single lab
    • Molecular basis of mesoderm suppression unidentified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TET3's many context-specific catalytic and scaffolding functions are coordinated and selected at the level of recruitment, isoform choice, and post-translational control across cell types remains unresolved.
  • No unified model linking CXXC isoform usage, partner recruitment, and PTMs to functional output
  • Structural basis for scaffolding interactions largely undetermined
  • In vivo relevance of several disease-context functions rests on single studies

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 6 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0000228 nuclear chromosome 4 GO:0005634 nucleus 4 GO:0005654 nucleoplasm 2
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-1430728 Metabolism 4 R-HSA-4839726 Chromatin organization 4 R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-73894 DNA Repair 2
Partners
CEBPDGLUD1HDAC1OGTPGC7/DPPA3PPARGC1ASIN3A
Complex memberships
SIN3A/HDAC1 corepressor complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 TET3 is the dioxygenase responsible for oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) on the paternal genome in mouse zygotes. TET3 is enriched specifically in the male pronucleus, and in Tet3-deficient zygotes, paternal-genome conversion of 5mC to 5hmC fails to occur. Deficiency of Tet3 also impedes demethylation of paternal Oct4 and Nanog genes and delays activation of a paternally derived Oct4 transgene in early embryos. Conditional knockout mice; immunofluorescence showing TET3 enrichment in male pronucleus; antibody staining for 5mC/5hmC in Tet3-deficient zygotes; transgene activation assay Nature High 21892189
2012 The Xenopus Tet3 CXXC domain is critical for specific genomic targeting, and both the enzymatic (5mC hydroxylase) activity and the CXXC domain are required for Tet3's biological function in eye and neural development. Tet3 directly regulates the 5mC/5hmC status at target gene promoters to control gene expression. Biochemical and structural studies of CXXC domain; in vivo Xenopus loss-of-function; domain-deletion mutants; 5mC/5hmC quantification at target promoters Cell High 23217707
2013 TET3 directly interacts with O-GlcNAc transferase (OGT) via its C-terminal H domain, and this interaction stabilizes OGT protein and promotes its localization to chromatin. TET3 is itself GlcNAcylated by OGT, although GlcNAcylation does not affect TET3's global 5mC hydroxylation activity. Affinity purification of FLAG-TET3 followed by mass spectrometry; co-immunoprecipitation with deletion mutants; chromatin fractionation; OGT stability assay Genes to cells Medium 24304661
2013 TET2 and TET3 directly interact with OGT and promote OGT enzymatic activity, leading to GlcNAcylation of HCF1 (a component of SET1/COMPASS), which is required for SET1/COMPASS integrity and H3K4me3 deposition at active promoters. TET2/3 and OGT co-localize on chromatin at active promoters enriched for H3K4me3. Co-immunoprecipitation; ChIP; GlcNAcylation assays; SET1/COMPASS integrity assays; Tet2 knockout mouse bone marrow tissue analysis The EMBO journal High 23353889
2013 PGC7 (Dppa3/Stella) interacts with TET3 both in vitro and in vivo to suppress TET3 enzymatic activity, thereby protecting DNA methylation at imprinting loci from TET3-dependent oxidation. In vitro binding assay; co-immunoprecipitation; enzymatic activity assay; genome-wide PGC7 binding analysis; methylation analysis at imprinting loci Nucleic acids research High 24322296
2013 Mouse Tet3 exists as alternative isoforms including a full-length isoform with an intrinsic CXXC domain (Tet3CXXC) and a form that lacks it. The CXXC domains of Tet1 and Tet3CXXC bind DNA with similar preference for cytosine modification state at a single CpG site in vitro. Tet3 also interacts with Cxxc4 (an adjacent encoded CXXC domain protein). Both Tet3 isoforms with and without CXXC domain hydroxylate genomic 5mC with similar activity in vivo. Alternative transcript identification; in vitro DNA binding assay; in vivo 5mC hydroxylation assay; co-immunoprecipitation for Tet3-Cxxc4 interaction PloS one Medium 23690950
2014 Genome-wide analysis in Tet3-deficient and DNA replication-inhibited zygotes showed that Tet3 facilitates demethylation largely by coupling with DNA replication, and contributes to demethylation of both paternal and maternal genomes. Replication-dependent dilution is the major contributor to demethylation, but Tet3 plays an important role particularly at certain loci including gene bodies and intergenic sequences. Genome-scale bisulfite sequencing of Tet3-depleted and DNA replication-inhibited zygotes; SNP-based allele discrimination; comparison of paternal and maternal methylation profiles Cell stem cell High 25280220
2014 Genome-wide bisulfite sequencing in TET3-deficient zygotes mapped TET3 oxidative demethylation targets to a subset of gene bodies and intergenic sequences. Unexpectedly, TET3 activity also protects certain CpG islands against methylation buildup. Loss of 5mC at gene bodies is associated with zygotic genome activation and increased transcriptional noise. Optimized bisulfite sequencing of control and TET3-deficient zygotes; SNP-based paternal allele analysis Cell reports High 25497087
2014 BMP7-induced reversal of kidney fibrosis is mediated specifically through Tet3-mediated hydroxymethylation of the hypermethylated Rasal1 promoter, restoring its expression and inhibiting fibroblast activation. Mouse kidney fibrosis model with BMP7 administration; siRNA knockdown of Tet3; 5hmC analysis at Rasal1 promoter; fibrosis markers Journal of the American Society of Nephrology Medium 24480825
2015 Haploinsufficiency of Tet3, not defective paternal 5mC oxidation per se, accounts for the developmental sublethality phenotype of maternal Tet3 knockout mice. Wild-type embryos reconstituted with paternal pronuclei that bypassed 5mC oxidation develop normally to adulthood, and genome-scale DNA methylation analysis showed hypermethylation in maternal Tet3 knockout embryos is largely resolved by blastocyst stage. Genetic rescue experiments; paternal pronucleus reconstruction bypassing 5mC oxidation; genome-scale DNA methylation analysis; heterozygous crosses Cell reports High 25640176
2015 Synaptic activity bidirectionally regulates neuronal Tet3 expression. TET3-mediated 5mC oxidation and base-excision repair (BER) regulate excitatory glutamatergic synaptic transmission in hippocampal neurons by controlling neuronal surface GluR1 levels. Knockdown of Tet3 or inhibition of BER elevated excitatory transmission, while overexpression of Tet3 or Tet1 catalytic domain decreased it. Dysregulation of Tet3 prevents homeostatic synaptic plasticity. shRNA knockdown; Tet3 overexpression; electrophysiology in hippocampal neurons; surface GluR1 quantification; BER inhibition; RNA-seq Nature neuroscience High 25915473
2015 TET3 localizes not only to the paternal pronucleus but also to the maternal pronucleus in mouse zygotes and oxidizes both paternal and maternal DNA, though less prominently in the female pronucleus. Genetic ablation of TET3 in oocytes results in neonatal sublethality but does not affect oocyte or embryonic development, indicating zygotic 5mC oxidation by maternal TET3 is required for neonatal growth but not embryonic development. Conditional knockout in oocytes; immunofluorescence for TET3 localization; 5mC/5hmC staining of both pronuclei; neonatal viability analysis Scientific reports Medium 26507142
2016 TET3 exists as three major isoforms; the full-length isoform (Tet3FL) contains an N-terminal CXXC domain that binds unmethylated CpGs but has highest affinity for 5-carboxylcytosine (5caC). Crystal structure of the CXXC domain bound to 5caC-DNA reveals the structural basis for CcaCG sequence recognition. Tet3FL localizes precisely at transcription start sites of genes involved in lysosome function, mRNA processing, and base-excision repair in neuronal cells. Crystal structure determination; in vitro DNA binding assays with different cytosine modifications; ChIP-seq in neuronal cells; isoform characterization Cell reports High 26774490
2016 TET3 negatively regulates IFN-β production in response to viral infection or poly(I:C) stimulation independently of its DNA demethylation catalytic activity. The catalytic domain of TET3 interacts with HDAC1 and SIN3A, enhancing their binding to the Ifnb1 promoter to suppress transcription. TET3 deletion; overexpression of catalytic-dead mutant; co-immunoprecipitation of TET3 with HDAC1 and SIN3A; ChIP at Ifnb1 promoter; antiviral response assays Cell reports Medium 27425624
2017 ATR-dependent DNA damage response leads to dynamic changes in 5hmC levels and TET3 enzymatic activity. TET3 is a substrate of ATR kinase. TET3-mediated 5mC-to-5hmC conversion is required for efficient DNA repair during ATR-dependent DDR; modulation of TET3 expression or activity affects DNA damage signaling, repair, and cell death. ATR kinase assay with TET3 as substrate; TET3 expression modulation; 5hmC level measurement after DNA damage; DNA repair and cell death assays EMBO reports Medium 28325772
2017 TET3 interacts with thyroid hormone receptors (TRα and TRβ) independently of its catalytic activity, stabilizing TRs on chromatin and promoting efficient binding to target genes and transcriptional activation. TET3 also interacts with other nuclear receptor superfamily members and enhances their association with chromatin. Co-immunoprecipitation of TET3 with TR isoforms; ChIP showing TR stability on chromatin with/without TET3; reporter gene assays; catalytic-dead TET3 mutant retaining TR interaction Proceedings of the National Academy of Sciences of the United States of America Medium 28716910
2019 TET3 binds to target gene promoters in hepatic stellate cells to induce demethylation and chromatin remodeling, upregulating multiple key TGF-β pathway genes including TGFB1. A positive feedback loop exists between TGF-β1 and TET3 in both HSCs and hepatocytes, driving liver fibrosis. ChIP showing TET3 binding at target promoters; bisulfite sequencing of promoter methylation; TET3 knockdown in human HSCs and mouse liver fibrosis model; TGF-β pathway gene expression analysis Cell reports Medium 32023451
2019 TET3 non-catalytically binds the paternal transcribed allele of the imprinted gene Snrpn in adult neural stem cells (NSCs), contributing to transcriptional repression of Snrpn. This prevents premature differentiation of NSCs into non-neurogenic astrocytes in the adult subventricular zone. BMP2 was identified as an effector of astrocytic terminal differentiation mediated by SNRPN. Tet3 conditional knockout in adult NSCs; allele-specific binding assay at Snrpn locus; neurosphere and differentiation assays; BMP2 rescue experiments Nature communications Medium 30979904
2020 CDK5 phosphorylates Tet3 at conserved serine residues S1310 and S1379 within its catalytic domain, altering its in vitro dioxygenase activity and changing the gene expression program during neuronal differentiation. Phospho-mutant Tet3 (S1310A/S1379A) shows different 5hmC distribution, differential binding to histone variant H2A.Z, and impaired activation of the neuronal gene BRN2. In vitro CDK5 kinase assay with TET3 as substrate; phospho-mutant stable expression in triple-KO ESCs; 5hmC mapping at BRN2 promoter; H2A.Z ChIP; neuronal differentiation assay Nucleic acids research High 31807777
2020 TET3 deficiency in adult postmitotic neurons (via Camk2a-CreERT2 conditional KO) results in increased anxiety-like behavior, hypercorticalism, and impaired hippocampal-dependent spatial orientation. Transcriptome analysis revealed dysregulation of glucocorticoid signaling pathway genes in the ventral hippocampus and upregulation of immediate early genes, with increased dendritic spine maturation in ventral CA1. Conditional inducible Tet3 KO in adult neurons (Camk2a-CreERT2); behavioral assays; RNA-seq of hippocampal subregions; dendritic spine morphology analysis Molecular psychiatry Medium 32103150
2021 In neurons, glutamate dehydrogenase (GDH), normally a mitochondrial enzyme, is redirected to the nucleus by Tet3 and produces α-ketoglutarate (αKG) on-site to supply Tet3 dioxygenase activity. GDH has a stimulatory effect on Tet3 demethylation activity, and neuronal activation increases nuclear αKG levels. Co-immunoprecipitation of Tet3-GDH; subcellular fractionation; nuclear αKG measurement; Tet3 activity assay in presence/absence of GDH; neuronal activation experiments Nature communications Medium 34215750
2022 TET3 dioxygenase expression is reduced in oocytes from diabetic/hyperglycemic mice and humans. Insufficient TET3-mediated demethylation in oocytes leads to persistent hypermethylation at paternal alleles of insulin secretion genes including glucokinase (Gck), impairing glucose-stimulated insulin secretion in offspring. Exogenous Tet3 mRNA injected into oocytes from hyperglycemic mice ameliorates this maternal effect. Mouse hyperglycemia model; oocyte TET3 conditional KO; bisulfite sequencing of Gck and other loci from zygote to adult; insulin secretion assays; mRNA rescue injection Nature High 35585240
2022 In AGRP neurons, TET3 dynamically associates with the Agrp promoter in response to leptin signaling, inducing 5hmC modification associated with a chromatin-modifying complex leading to transcription inhibition of Agrp. CRISPR-mediated ablation of Tet3 specifically in AGRP neurons activates these neurons, upregulates Agrp, Npy, and Slc32a1 expression, and causes hyperphagia, obesity, diabetes, and reduced stress-like behaviors. CRISPR-mediated conditional Tet3 ablation in AGRP neurons; ChIP showing TET3 association with Agrp promoter; 5hmC modification assay at Agrp promoter; leptin signaling experiments; behavioral and metabolic phenotyping; human neuronal cell validation The Journal of clinical investigation High 36189793
2022 TET3 forms a complex with PGC-1α in skeletal muscle and interferes with PGC-1α phosphorylation, leading to PGC-1α destabilization. Muscle-specific Tet3 KO increases PGC-1α levels, improves mitochondrial respiration and insulin sensitivity. TET3 expression is elevated in skeletal muscles of humans with type 2 diabetes. Muscle-specific Tet3 KO mice; Co-IP of TET3-PGC-1α complex; in vitro phosphorylation/degradation assay; RNA-seq; mitochondrial respiration assay; insulin tolerance tests Diabetologia Medium 38216792
2023 SUMO1 modifies TET3 at lysine sites K479, K758, K1012, K1188, K1397, and K1623, increasing TET3 protein stability without changing its nuclear localization, thereby sensitizing colorectal cancer cells to radiation therapy. Co-immunoprecipitation of TET3 with SUMO1 and SUMO2/3; binding domain mapping (833-1795 AA); immunofluorescence for co-localization; TET3 stability assays with/without SUMOylation; radiation sensitivity assays International journal of radiation oncology, biology, physics Medium 37244630
2024 TET3 has distinct catalytic-dependent and catalytic-independent roles in neuroectoderm specification: catalytic activity is important for activation of neural genes (with hyper-DMRs linked to downregulated neural genes), while non-catalytic functions suppress mesodermal programs. TET3 directly regulates the maintenance methyltransferase Dnmt1, which is downregulated in TET3-deficient NE cells and may contribute to increased DNA hypomethylation. TET3 catalytic-mutant (Tet3m/m) and knockout (Tet3-/-) mouse ESCs differentiated to neuroectoderm; whole-genome bisulfite sequencing; RNA-seq; comparison of catalytic vs. null phenotypes Communications biology Medium 38580843
2024 TET3 promotes endometriosis by overexpression in pathogenic macrophages. TET3 overexpression stimulates proinflammatory cytokine production via inhibition of let-7 miRNA expression (feedback mechanism). These TET3-overexpressing macrophages depend on TET3 for survival. The small molecule Bobcat339 triggers TET3 protein degradation dependent on VHL E3 ubiquitin ligase, whose expression is also upregulated in TET3-overexpressing macrophages. Myeloid-specific Tet3 ablation in mice; Bobcat339 treatment; VHL dependency assay; let-7 miRNA measurement; macrophage survival assays; endometriosis mouse model The Journal of clinical investigation Medium 39141428
2020 TET3 loss-of-function (missense variants in the catalytic domain) causes a Mendelian neurodevelopmental disorder (TET3 deficiency/Beck-Fahrner syndrome) with intellectual disability, hypotonia, autism traits, and movement disorders. Missense variants in the catalytic domain show hypomorphic dioxygenase activity in a catalytic activity assay. Patient variant identification; catalytic activity assay for missense variants; clinical phenotyping of 11 cases from 8 families American journal of human genetics Medium 31928709
2021 TET3 deficiency in whole blood produces a genome-wide DNA hypermethylation episignature. This episignature can distinguish TET3-deficient individuals from controls and can be used to determine pathogenicity of variants of uncertain significance, establishing a functional readout for TET3 catalytic loss-of-function in human disease. Genome-wide DNA methylation profiling (array) of whole blood from TET3-deficient patients; episignature validation against 46 other disorders; correlation with DNMT1-activating mutations NPJ genomic medicine Medium 34750377
2017 METH administration increases TET3 binding at Avp intragenic regions in rat nucleus accumbens, accompanied by increased DNA hydroxymethylation at these sites and increased Avp mRNA expression. TET inhibition by IQD blocked METH-induced Avp expression, establishing TET3-dependent DNA hydroxymethylation as a mechanism for neuropeptide gene regulation. ChIP for TET3 binding at Avp locus; 5hmC immunoprecipitation; TET inhibitor (IQD) treatment; qRT-PCR for Avp expression Molecular neurobiology Medium 28842817
2019 Integrin α6-FAK signaling activates STAT3, which directly regulates TET3 expression. TET3 in turn mediates 5hmC upregulation at the promoters of tumorigenic genes including c-Myc in glioma stem cells, maintaining their stemness. STAT3 and TET3 are co-localized with 5hmC in GSC clusters. STAT3 ChIP at TET3 promoter; TET3 knockdown in GSCs; 5hmC ChIP at c-Myc and other gene promoters; integrin α6-FAK pathway perturbation; in vivo tumor experiments Oncogene Medium 31819166
2020 TET3 non-catalytically binds to the paternal allele of Snrpn, and specifically in neural progenitors, Tet3 knockdown leads to de-repression of pluripotency genes (Oct4, Nanog, Tcl1) with concomitant hypomethylation, while also causing hypermethylation at neurogenesis-related gene loci and imprinting control regions, suggesting TET3 is needed to maintain neural stem cell identity. Inducible Tet3 knockdown in NPCs; RNA-seq; genome-scale DNA methylation (RRBS); OCT4 immunostaining; aggregate formation assay Cellular and molecular life sciences Medium 31646359
2023 Bmal1, a circadian clock transcription factor, acts as a gatekeeper of neuroepigenetic responses by limiting Tet3 expression and restricting 5hmC modifications in dorsal root ganglia neurons after axonal injury. Bmal1 conditional deletion in neurons increases Tet3 expression and 5hmC levels, enhancing axon regeneration. Diurnal oscillation of Tet3 and 5hmC levels is observed in DRG neurons. Conditional Bmal1 deletion in neurons; in vitro and in vivo neurite outgrowth assays; 5hmC profiling (DhMR analysis); Tet3 expression measurement; circadian 5hmC oscillation analysis Nature communications Medium 37620297
2022 TET3 promotes targeted DNA demethylation at adipocyte-specific loci carrying the C/EBP binding motif by being recruited there via the transcription factor C/EBPδ. This TET3-catalyzed demethylation activates key adipogenic genes and drives adipocyte differentiation. Ectopic TET3 expression potentiates adipocyte differentiation in vitro and in vivo and recovers downregulated adipogenic potential in aged animals. Whole-genome bisulfite sequencing during adipogenesis; Co-immunoprecipitation of C/EBPδ-TET3; ChIP showing TET3 recruitment to C/EBP binding motifs; TET3 overexpression in vitro and in vivo Nature metabolism High 35788760
2024 TET3 loss in cardiac fibroblasts leads to spontaneous DNA damage and, in the presence of TGF-β, shifts DNA double-strand break repair from homologous recombination (HR) to non-homologous end joining (NHEJ), increasing fibroblast proliferation. TET3 is recruited to H2O2-induced DNA double-strand breaks in mouse cardiac fibroblasts and promotes HR repair. Overexpression of TET3 counteracts TGF-β-induced fibroblast proliferation and restores HR repair efficiency. In vitro and in vivo cardiac fibrosis models; TET3 KO/overexpression; DNA damage repair pathway assays (HR vs NHEJ); TET3 recruitment to DSBs; human cardiac fibrosis tissue analysis Clinical epigenetics Medium 39192299

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 904 21892189
2013 TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. The EMBO journal 411 23353889
2012 Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 207 23217707
2014 Tet3 and DNA replication mediate demethylation of both the maternal and paternal genomes in mouse zygotes. Cell stem cell 204 25280220
2012 Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians. American journal of human genetics 175 23273568
2015 Tet3 regulates synaptic transmission and homeostatic plasticity via DNA oxidation and repair. Nature neuroscience 154 25915473
2014 Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation. Proceedings of the National Academy of Sciences of the United States of America 153 24757058
2019 Loss of TET2 and TET3 in regulatory T cells unleashes effector function. Nature communications 138 31043609
2016 Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility. eLife 135 27869616
2014 Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. Journal of the American Society of Nephrology : JASN 114 24480825
2022 Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency. Nature 107 35585240
2016 Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration. Cell reports 105 26774490
2015 Simultaneous deletion of the methylcytosine oxidases Tet1 and Tet3 increases transcriptome variability in early embryogenesis. Proceedings of the National Academy of Sciences of the United States of America 99 26199412
2014 Genome-wide bisulfite sequencing in zygotes identifies demethylation targets and maps the contribution of TET3 oxidation. Cell reports 99 25497087
2020 Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity. Nature immunology 76 32572241
2020 Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency. American journal of human genetics 75 31928709
2013 TET3-OGT interaction increases the stability and the presence of OGT in chromatin. Genes to cells : devoted to molecular & cellular mechanisms 75 24304661
2015 Overlapping Requirements for Tet2 and Tet3 in Normal Development and Hematopoietic Stem Cell Emergence. Cell reports 72 26257178
2016 Downregulation of TLX induces TET3 expression and inhibits glioblastoma stem cell self-renewal and tumorigenesis. Nature communications 69 26838672
2014 Critical role of Tet3 in neural progenitor cell maintenance and terminal differentiation. Molecular neurobiology 69 24838624
2015 Induction of Tet3-dependent Epigenetic Remodeling by Low-dose Hydralazine Attenuates Progression of Chronic Kidney Disease. EBioMedicine 65 25717475
2014 MicroRNA-15b promotes neurogenesis and inhibits neural progenitor proliferation by directly repressing TET3 during early neocortical development. EMBO reports 63 25344561
2020 A Positive Feedback Loop of TET3 and TGF-β1 Promotes Liver Fibrosis. Cell reports 60 32023451
2019 Epigenetic downregulation of TET3 reduces genome-wide 5hmC levels and promotes glioblastoma tumorigenesis. International journal of cancer 58 31211412
2013 PGC7 suppresses TET3 for protecting DNA methylation. Nucleic acids research 56 24322296
2016 TET3 inhibits TGF-β1-induced epithelial-mesenchymal transition by demethylating miR-30d precursor gene in ovarian cancer cells. Journal of experimental & clinical cancer research : CR 51 27141829
2015 Maternal TET3 is dispensable for embryonic development but is required for neonatal growth. Scientific reports 50 26507142
2020 Tet3 ablation in adult brain neurons increases anxiety-like behavior and regulates cognitive function in mice. Molecular psychiatry 49 32103150
2017 TET3-mediated DNA oxidation promotes ATR-dependent DNA damage response. EMBO reports 49 28325772
2016 TET3 Inhibits Type I IFN Production Independent of DNA Demethylation. Cell reports 48 27425624
2012 Transcriptional activation of transposable elements in mouse zygotes is independent of Tet3-mediated 5-methylcytosine oxidation. Cell research 48 23184059
2019 Glyphosate Primes Mammary Cells for Tumorigenesis by Reprogramming the Epigenome in a TET3-Dependent Manner. Frontiers in genetics 43 31611907
2015 Tet3 mediates stable glucocorticoid-induced alterations in DNA methylation and Dnmt3a/Dkk1 expression in neural progenitors. Cell death & disease 42 26086966
2018 A miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset. Nature communications 41 30575719
2017 Methamphetamine Induces TET1- and TET3-Dependent DNA Hydroxymethylation of Crh and Avp Genes in the Rat Nucleus Accumbens. Molecular neurobiology 41 28842817
2019 Tet3 regulates cellular identity and DNA methylation in neural progenitor cells. Cellular and molecular life sciences : CMLS 40 31646359
2021 TET3 promotes AML growth and epigenetically regulates glucose metabolism and leukemic stem cell associated pathways. Leukemia 38 34462525
2017 Epigenetic silencing of TET2 and TET3 induces an EMT-like process in melanoma. Oncotarget 38 27852070
2017 CRISPR-Cas9-mediated genome editing in one blastomere of two-cell embryos reveals a novel Tet3 function in regulating neocortical development. Cell research 38 28429771
2015 Haploinsufficiency, but not defective paternal 5mC oxidation, accounts for the developmental defects of maternal Tet3 knockouts. Cell reports 38 25640176
2020 TET3 regulates DNA hydroxymethylation of neuroprotective genes following focal ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 37 32380888
2019 Integrin α6 signaling induces STAT3-TET3-mediated hydroxymethylation of genes critical for maintenance of glioma stem cells. Oncogene 35 31819166
2013 Intrinsic and extrinsic connections of Tet3 dioxygenase with CXXC zinc finger modules. PloS one 35 23690950
2019 TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn. Nature communications 34 30979904
2017 TET3 Mediates Alterations in the Epigenetic Marker 5hmC and Akt pathway in Steroid-Associated Osteonecrosis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 27627619
2016 Tet3-Mediated DNA Demethylation Contributes to the Direct Conversion of Fibroblast to Functional Neuron. Cell reports 29 27880907
2014 TET3 mediates the activation of human hepatic stellate cells via modulating the expression of long non-coding RNA HIF1A-AS1. International journal of clinical and experimental pathology 29 25550811
2021 Berberine inhibits the Warburg effect through TET3/miR-145/HK2 pathways in ovarian cancer cells. Journal of Cancer 28 33391417
2018 Association of TET3 epigenetic inactivation with head and neck cancer. Oncotarget 28 29849955
2020 Epigenetic induction of tumor stemness via the lipopolysaccharide-TET3-HOXB2 signaling axis in esophageal squamous cell carcinoma. Cell communication and signaling : CCS 27 32014008
2022 Targeted erasure of DNA methylation by TET3 drives adipogenic reprogramming and differentiation. Nature metabolism 25 35788760
2018 Retrieval-Induced Upregulation of Tet3 in Pyramidal Neurons of the Dorsal Hippocampus Mediates Cocaine-Associated Memory Reconsolidation. The international journal of neuropsychopharmacology 25 29106571
2012 PGC7, H3K9me2 and Tet3: regulators of DNA methylation in zygotes. Cell research 25 22868271
2021 Redirected nuclear glutamate dehydrogenase supplies Tet3 with α-ketoglutarate in neurons. Nature communications 24 34215750
2021 Two families with TET3-related disorder showing neurodevelopmental delay with craniofacial dysmorphisms. Journal of human genetics 24 34719681
2020 The KRAS/Lin28B axis maintains stemness of pancreatic cancer cells via the let-7i/TET3 pathway. Molecular oncology 24 33107691
2017 Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin. Proceedings of the National Academy of Sciences of the United States of America 24 28716910
2022 TET3 epigenetically controls feeding and stress response behaviors via AGRP neurons. The Journal of clinical investigation 22 36189793
2021 Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood. NPJ genomic medicine 22 34750377
2024 TET3-overexpressing macrophages promote endometriosis. The Journal of clinical investigation 21 39141428
2023 TET2 and TET3 loss disrupts small intestine differentiation and homeostasis. Nature communications 21 37414790
2019 Tet3 is required for normal in vitro fertilization preimplantation embryos development of bovine. Molecular reproduction and development 20 30624819
2019 Somatic mutation and loss of expression of a candidate tumor suppressor gene TET3 in gastric and colorectal cancers. Pathology, research and practice 19 31859118
2023 A small-molecule degrader of TET3 as treatment for anorexia nervosa in an animal model. Proceedings of the National Academy of Sciences of the United States of America 18 37036983
2020 Phosphorylation of Tet3 by cdk5 is critical for robust activation of BRN2 during neuronal differentiation. Nucleic acids research 18 31807777
2022 Deficiency of Tet3 in nucleus accumbens enhances fear generalization and anxiety-like behaviors in mice. Brain pathology (Zurich, Switzerland) 17 35612904
2021 TET3- and OGT-Dependent Expression of Genes Involved in Epithelial-Mesenchymal Transition in Endometrial Cancer. International journal of molecular sciences 17 34948036
2020 TET3 overexpression facilitates DNA reprogramming and early development of bovine SCNT embryos. Reproduction (Cambridge, England) 17 32544877
2018 Overexpression of Tet3 in donor cells enhances goat somatic cell nuclear transfer efficiency. The FEBS journal 17 29791079
2012 H3K9me2 attracts PGC7 in the zygote to prevent Tet3-mediated oxidation of 5-methylcytosine. Journal of molecular cell biology 17 22750790
2023 Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons. Nature communications 16 37620297
2023 TET3-mediated DNA oxidation is essential for intestinal epithelial cell response to stressors. Proceedings of the National Academy of Sciences of the United States of America 16 37669386
2017 Dynamic expression of TET1, TET2, and TET3 dioxygenases in mouse and human placentas throughout gestation. Placenta 16 29108636
2019 Endogenous epitope-tagging of Tet1, Tet2 and Tet3 identifies TET2 as a naïve pluripotency marker. Life science alliance 15 31582397
2024 Epigenetic Regulatory Axis MIR22-TET3-MTRNR2L2 Represses Fibroblast-Like Synoviocyte-Mediated Inflammation in Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, N.J.) 14 38221658
2021 Loss of miR-29a impairs decidualization of endometrial stromal cells by TET3 mediated demethylation of Col1A1 promoter. iScience 13 34568789
2020 TET3 controls the expression of the H3K27me3 demethylase Kdm6b during neural commitment. Cellular and molecular life sciences : CMLS 13 32405722
2024 Catalytic-dependent and -independent roles of TET3 in the regulation of specific genetic programs during neuroectoderm specification. Communications biology 12 38580843
2023 ZMIZ1 Upregulation of TET3-Mediated Hydroxymethylation Induces M2 Polarization of Kupffer Cells in Hepatocellular Carcinogenesis by Mediating Notch1/c-Myc Signaling. Laboratory investigation; a journal of technical methods and pathology 12 37839636
2024 Loss of tet methyl cytosine dioxygenase 3 (TET3) enhances cardiac fibrosis via modulating the DNA damage repair response. Clinical epigenetics 11 39192299
2022 Tet3 Deletion in Adult Brain Neurons of Female Mice Results in Anxiety-like Behavior and Cognitive Impairments. Molecular neurobiology 11 35665901
2022 TET3 Mediates 5hmC Level and Promotes Tumorigenesis by Activating AMPK Pathway in Papillary Thyroid Cancer. International journal of endocrinology 11 35755313
2022 miR-488-5p mitigates hepatic stellate cell activation and hepatic fibrosis via suppressing TET3 expression. Hepatology international 11 36001230
2016 TET1 and TET3 are essential in induction of Th2-type immunity partly through regulation of IL-4/13A expression in zebrafish model. Gene 11 27418527
2025 MYC/TET3-Regulated TMEM65 Activates OXPHOS-SERPINB3 Pathway to Promote Progression and Cisplatin Resistance in Triple-Negative Breast Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10 40546127
2022 Transglutaminase 3 Attenuates Skin Inflammation in Psoriasis by Inhibiting NF-κB Activation through Phosphorylated STAT3-TET3 Signaling. The Journal of investigative dermatology 10 35545140
2020 The microRNA/TET3/REST axis is required for olfactory globose basal cell proliferation and male behavior. EMBO reports 10 32677323
2019 Tet3 enhances IL-6 expression through up-regulation of 5-hmC in IL-6 promoter in chronic hypoxia induced atherosclerosis in offspring rats. Life sciences 10 31252000
2024 Skeletal muscle TET3 promotes insulin resistance through destabilisation of PGC-1α. Diabetologia 9 38216792
2022 Role of DNA dioxygenase Ten-Eleven translocation 3 (TET3) in rheumatoid arthritis progression. Arthritis research & therapy 9 36114544
2020 Double dissociation of inhibitory effects between the hippocampal TET1 and TET3 in the acquisition of morphine self-administration in rats. Addiction biology 9 32031744
2024 TET3-mediated DNA demethylation modification activates SHP2 expression to promote endometrial cancer progression through the EGFR/ERK pathway. Journal of gynecologic oncology 8 38456588
2024 Pan-cancer analyses reveal the molecular and clinical characteristics of TET family members and suggests that TET3 maybe a potential therapeutic target. Frontiers in pharmacology 8 39104395
2023 TET3-mediated DNA demethylation and chromatin remodeling regulate T-2 toxin-induced human CYP1A1 expression and cytotoxicity in HepG2 cells. Biochemical pharmacology 8 36948362
2023 SUMO1 Modification Stabilizes TET3 Protein and Increases Colorectal Cancer Radiation Therapy Sensitivity. International journal of radiation oncology, biology, physics 8 37244630
2023 The novel oncogenic factor TET3 combines with AHR to promote thyroid cancer lymphangiogenesis via the HIF-1α/VEGF signaling pathway. Cancer cell international 8 37718440
2021 TET3 dioxygenase modulates gene conversion at the avian immunoglobulin variable region via demethylation of non-CpG sites in pseudogene templates. Genes to cells : devoted to molecular & cellular mechanisms 8 33421268
2021 Overexpression of Long Non-Coding RNA MIR22HG Represses Proliferation and Enhances Apoptosis via miR-629-5p/TET3 Axis in Osteosarcoma Cells. Journal of microbiology and biotechnology 8 34373436
2020 Demethylation of the RB1 promoter concomitant with reactivation of TET2 and TET3 impairs gastric carcinogenesis in K19-Wnt1/C2mE transgenic mice. Life sciences 8 33058920
2019 Identification and validation of mRNA 3'untranslated regions of DNMT3B and TET3 as novel competing endogenous RNAs of the tumor suppressor PTEN. International journal of oncology 8 31894272

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