{"gene":"TET3","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2011,"finding":"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.","method":"Conditional knockout mice; immunofluorescence showing TET3 enrichment in male pronucleus; antibody staining for 5mC/5hmC in Tet3-deficient zygotes; transgene activation assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined molecular phenotype (loss of 5hmC on paternal genome), specific localization to male pronucleus, replicated by multiple subsequent labs","pmids":["21892189"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Biochemical and structural studies of CXXC domain; in vivo Xenopus loss-of-function; domain-deletion mutants; 5mC/5hmC quantification at target promoters","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of CXXC domain, in vitro enzymatic assay, mutagenesis of catalytic domain and CXXC domain, in vivo developmental phenotype","pmids":["23217707"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Affinity purification of FLAG-TET3 followed by mass spectrometry; co-immunoprecipitation with deletion mutants; chromatin fractionation; OGT stability assay","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with deletion mapping, MS identification of OGT, functional chromatin localization assay; single lab","pmids":["24304661"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation; ChIP; GlcNAcylation assays; SET1/COMPASS integrity assays; Tet2 knockout mouse bone marrow tissue analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP co-localization, functional GlcNAcylation assay, SET1/COMPASS integrity, validated in KO mouse tissue; multiple orthogonal methods","pmids":["23353889"],"is_preprint":false},{"year":2013,"finding":"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.","method":"In vitro binding assay; co-immunoprecipitation; enzymatic activity assay; genome-wide PGC7 binding analysis; methylation analysis at imprinting loci","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding and enzymatic suppression assay, co-IP in vivo, functional methylation readout; single lab but multiple orthogonal methods","pmids":["24322296"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Alternative transcript identification; in vitro DNA binding assay; in vivo 5mC hydroxylation assay; co-immunoprecipitation for Tet3-Cxxc4 interaction","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding assay, in vivo hydroxylation, Co-IP for partner interaction; single lab","pmids":["23690950"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Genome-scale bisulfite sequencing of Tet3-depleted and DNA replication-inhibited zygotes; SNP-based allele discrimination; comparison of paternal and maternal methylation profiles","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — genome-wide bisulfite sequencing in genetic KO combined with pharmacological replication inhibition, allele-resolved; multiple labs replicated Tet3's role","pmids":["25280220"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Optimized bisulfite sequencing of control and TET3-deficient zygotes; SNP-based paternal allele analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — genome-wide bisulfite sequencing with genetic KO, allele-resolved; single lab but comprehensive genomic coverage","pmids":["25497087"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Mouse kidney fibrosis model with BMP7 administration; siRNA knockdown of Tet3; 5hmC analysis at Rasal1 promoter; fibrosis markers","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA) with defined molecular phenotype at specific locus; in vivo model; single lab","pmids":["24480825"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Genetic rescue experiments; paternal pronucleus reconstruction bypassing 5mC oxidation; genome-scale DNA methylation analysis; heterozygous crosses","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — genome-scale methylation analysis, genetic rescue with pronucleus reconstruction, multiple cross combinations; single lab but rigorous design with internal controls","pmids":["25640176"],"is_preprint":false},{"year":2015,"finding":"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.","method":"shRNA knockdown; Tet3 overexpression; electrophysiology in hippocampal neurons; surface GluR1 quantification; BER inhibition; RNA-seq","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional manipulation (KD and OE), electrophysiology, surface receptor quantification, BER pathway inhibition, RNA-seq; multiple orthogonal methods","pmids":["25915473"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Conditional knockout in oocytes; immunofluorescence for TET3 localization; 5mC/5hmC staining of both pronuclei; neonatal viability analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined phenotype, direct localization imaging; single lab","pmids":["26507142"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Crystal structure determination; in vitro DNA binding assays with different cytosine modifications; ChIP-seq in neuronal cells; isoform characterization","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, in vitro binding affinity measurements, genome-wide ChIP-seq in neuronal cells; single lab but multiple orthogonal methods","pmids":["26774490"],"is_preprint":false},{"year":2016,"finding":"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.","method":"TET3 deletion; overexpression of catalytic-dead mutant; co-immunoprecipitation of TET3 with HDAC1 and SIN3A; ChIP at Ifnb1 promoter; antiviral response assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic-dead mutant establishing non-catalytic function, Co-IP of HDAC1/SIN3A, ChIP at target promoter; single lab","pmids":["27425624"],"is_preprint":false},{"year":2017,"finding":"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.","method":"ATR kinase assay with TET3 as substrate; TET3 expression modulation; 5hmC level measurement after DNA damage; DNA repair and cell death assays","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified TET3 as ATR substrate, functional consequences of TET3 modulation on DDR; single lab","pmids":["28325772"],"is_preprint":false},{"year":2017,"finding":"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.","method":"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","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, functional transcriptional assays, catalytic-dead mutant; single lab","pmids":["28716910"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at specific promoters, bisulfite sequencing, KD with defined phenotype in vivo and in vitro; single lab","pmids":["32023451"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Tet3 conditional knockout in adult NSCs; allele-specific binding assay at Snrpn locus; neurosphere and differentiation assays; BMP2 rescue experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined differentiation phenotype, allele-specific binding, identification of downstream effector; single lab","pmids":["30979904"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay establishing CDK5 as TET3 kinase, phospho-mutant in vivo, 5hmC mapping, H2A.Z ChIP, functional neuronal differentiation; single lab but multiple orthogonal methods","pmids":["31807777"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Conditional inducible Tet3 KO in adult neurons (Camk2a-CreERT2); behavioral assays; RNA-seq of hippocampal subregions; dendritic spine morphology analysis","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined behavioral and transcriptomic phenotype; single lab","pmids":["32103150"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation of Tet3-GDH; subcellular fractionation; nuclear αKG measurement; Tet3 activity assay in presence/absence of GDH; neuronal activation experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing Tet3-GDH interaction, nuclear localization of GDH, functional stimulation of Tet3 activity; single lab","pmids":["34215750"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Mouse hyperglycemia model; oocyte TET3 conditional KO; bisulfite sequencing of Gck and other loci from zygote to adult; insulin secretion assays; mRNA rescue injection","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic KO, mRNA rescue, bisulfite sequencing across development, functional metabolic phenotype; multiple orthogonal approaches in single rigorous study","pmids":["35585240"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR conditional KO, ChIP at specific promoter, 5hmC modification assay, leptin signaling link, validated in human cells; multiple orthogonal methods","pmids":["36189793"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Diabetologia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing complex, in vitro phosphorylation assay, muscle-specific KO with functional metabolic phenotype; single lab","pmids":["38216792"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"International journal of radiation oncology, biology, physics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, functional stability assay, site-specific lysine identification; single lab","pmids":["37244630"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — catalytic-mutant vs. full KO genetic dissection, genome-wide bisulfite sequencing, RNA-seq; single lab","pmids":["38580843"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Myeloid-specific Tet3 ablation in mice; Bobcat339 treatment; VHL dependency assay; let-7 miRNA measurement; macrophage survival assays; endometriosis mouse model","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — myeloid-specific KO and pharmacological degradation, VHL-dependent degradation mechanism, let-7 feedback assay; single lab","pmids":["39141428"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Patient variant identification; catalytic activity assay for missense variants; clinical phenotyping of 11 cases from 8 families","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional catalytic assay for human variants, clinical genetics; single study but multiple independent families","pmids":["31928709"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Genome-wide DNA methylation profiling (array) of whole blood from TET3-deficient patients; episignature validation against 46 other disorders; correlation with DNMT1-activating mutations","journal":"NPJ genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide methylation in human patients with defined TET3 variants, functional validation; single study","pmids":["34750377"],"is_preprint":false},{"year":2017,"finding":"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.","method":"ChIP for TET3 binding at Avp locus; 5hmC immunoprecipitation; TET inhibitor (IQD) treatment; qRT-PCR for Avp expression","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing TET3 binding, 5hmC measurement, pharmacological inhibition confirming TET3 dependence; single lab","pmids":["28842817"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for STAT3 at TET3 promoter, 5hmC ChIP at downstream targets, TET3 KD with in vivo phenotype; single lab","pmids":["31819166"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Inducible Tet3 knockdown in NPCs; RNA-seq; genome-scale DNA methylation (RRBS); OCT4 immunostaining; aggregate formation assay","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible KD, genome-scale methylation, transcriptomic profiling; single lab","pmids":["31646359"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Conditional Bmal1 deletion in neurons; in vitro and in vivo neurite outgrowth assays; 5hmC profiling (DhMR analysis); Tet3 expression measurement; circadian 5hmC oscillation analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, genome-wide 5hmC profiling, functional axon growth assay, circadian oscillation measurement; single lab","pmids":["37620297"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"Nature metabolism","confidence":"High","confidence_rationale":"Tier 1 / Moderate — WGBS, Co-IP of transcription factor-TET3, ChIP of TET3 at specific loci, functional adipogenic assays in vitro and in vivo; multiple orthogonal methods","pmids":["35788760"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TET3 recruitment to DSBs, HR/NHEJ pathway shift assay, KO and OE functional experiments; single lab","pmids":["39192299"],"is_preprint":false}],"current_model":"TET3 is a methylcytosine dioxygenase that converts 5mC to 5hmC (and further oxidized derivatives) via an α-ketoglutarate-dependent mechanism; it is the predominant TET enzyme in oocytes, zygotes, and mature neurons, where it drives paternal (and to a lesser extent maternal) genome demethylation coupled to DNA replication, with its genomic targeting mediated by an intrinsic CXXC domain that preferentially binds 5-carboxylcytosine. Beyond its catalytic role, TET3 acts as a scaffold: it recruits OGT to chromatin (promoting H3K4me3 via SET1/COMPASS), interacts with HDAC1/SIN3A to suppress IFN-β independently of demethylation, stabilizes thyroid hormone receptors on chromatin, is recruited to DNA double-strand breaks to promote homologous recombination repair, and is phosphorylated by CDK5 and SUMOylated by SUMO1 to modulate its activity and stability. In neurons, TET3 is a synaptic activity sensor that controls surface GluR1 levels and homeostatic plasticity, and its nuclear α-ketoglutarate supply is maintained by a direct interaction with glutamate dehydrogenase redirected from mitochondria. In metabolic tissues, TET3 destabilizes PGC-1α in skeletal muscle to promote insulin resistance, and in AGRP neurons it associates with the Agrp promoter in response to leptin to restrict feeding."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2011,"claim":"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","pmids":["21892189"],"confidence":"High","gaps":["Did not resolve genome-wide vs locus-specific demethylation contribution","Mechanism of pronuclear targeting unaddressed"]},{"year":2012,"claim":"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","pmids":["23217707"],"confidence":"High","gaps":["Mammalian CXXC isoform usage not fully resolved here","Direct genomic binding map absent"]},{"year":2013,"claim":"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","pmids":["24304661","23353889"],"confidence":"High","gaps":["Whether this axis operates in zygotic reprogramming untested","Direct chromatin recruitment determinants unclear"]},{"year":2013,"claim":"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","pmids":["24322296"],"confidence":"High","gaps":["Stoichiometry and structural basis of inhibition unknown","Single lab"]},{"year":2014,"claim":"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","pmids":["25280220","25497087"],"confidence":"High","gaps":["Relative weighting of active vs passive demethylation per locus class incomplete","Mechanism of CpG-island protection unexplained"]},{"year":2015,"claim":"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","pmids":["25640176"],"confidence":"High","gaps":["Which dosage-sensitive TET3 functions cause sublethality unidentified"]},{"year":2015,"claim":"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","pmids":["25915473"],"confidence":"High","gaps":["Direct genomic targets controlling GluR1 not mapped","Link between BER and receptor trafficking mechanistically incomplete"]},{"year":2016,"claim":"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","pmids":["26774490"],"confidence":"High","gaps":["Functional consequence of 5caC preference in vivo unclear","Isoform-specific targeting in non-neuronal cells untested"]},{"year":2016,"claim":"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","pmids":["27425624"],"confidence":"Medium","gaps":["Single lab","How catalytic domain selects the Ifnb1 locus unknown"]},{"year":2017,"claim":"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","pmids":["28325772"],"confidence":"Medium","gaps":["Phosphosites and their functional effect not mapped","Direct recruitment to lesions not shown here"]},{"year":2017,"claim":"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","pmids":["28716910"],"confidence":"Medium","gaps":["Single lab","Generality across nuclear receptor superfamily incompletely defined"]},{"year":2019,"claim":"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","pmids":["30979904","31646359"],"confidence":"Medium","gaps":["Single lab","Mechanism of allele-specific recognition unresolved"]},{"year":2020,"claim":"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","pmids":["31807777"],"confidence":"High","gaps":["In vivo relevance of phosphosites untested","How phosphorylation alters H2A.Z binding mechanistically unclear"]},{"year":2020,"claim":"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","pmids":["31928709","32103150"],"confidence":"Medium","gaps":["Single clinical cohort","Molecular targets driving behavioral phenotypes not defined"]},{"year":2021,"claim":"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","pmids":["34215750"],"confidence":"Medium","gaps":["Single lab","Mechanism of GDH nuclear redirection unresolved"]},{"year":2021,"claim":"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","pmids":["34750377"],"confidence":"Medium","gaps":["Single study","Tissue-specificity of the episignature not established"]},{"year":2022,"claim":"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","pmids":["35585240"],"confidence":"High","gaps":["Human translation limited to expression correlation","Other affected loci beyond Gck incompletely cataloged"]},{"year":2022,"claim":"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","pmids":["36189793","38216792","35788760"],"confidence":"High","gaps":["Whether these roles share a common recruitment logic unclear","Reconciling activating vs repressive outcomes mechanistically incomplete"]},{"year":2024,"claim":"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","pmids":["39192299"],"confidence":"Medium","gaps":["Single lab","Whether recruitment is catalytic or scaffolding not resolved"]},{"year":2024,"claim":"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","pmids":["38580843"],"confidence":"Medium","gaps":["Single lab","Molecular basis of mesoderm suppression unidentified"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,6,12,18,27]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,18]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,12,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[13,15,22,33]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,11,24]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,3,12,18]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[3,12]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,3,12,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,13,15,22,33]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[14,34]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,25,33]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,18,20]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[21,22,23,33]}],"complexes":["SIN3A/HDAC1 corepressor complex"],"partners":["OGT","HDAC1","SIN3A","PGC7/DPPA3","PPARGC1A","CEBPD","GLUD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43151","full_name":"Methylcytosine dioxygenase TET3","aliases":[],"length_aa":1795,"mass_kda":193.7,"function":"Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in epigenetic chromatin reprogramming in the zygote following fertilization (PubMed:31928709). Also mediates subsequent conversion of 5hmC into 5-formylcytosine (5fC), and conversion of 5fC to 5-carboxylcytosine (5caC). Conversion of 5mC into 5hmC, 5fC and 5caC probably constitutes the first step in cytosine demethylation (By similarity). Selectively binds to the promoter region of target genes and contributes to regulate the expression of numerous developmental genes (PubMed:23217707). In zygotes, DNA demethylation occurs selectively in the paternal pronucleus before the first cell division, while the adjacent maternal pronucleus and certain paternally-imprinted loci are protected from this process. Participates in DNA demethylation in the paternal pronucleus by mediating conversion of 5mC into 5hmC, 5fC and 5caC. Does not mediate DNA demethylation of maternal pronucleus because of the presence of DPPA3/PGC7 on maternal chromatin that prevents TET3-binding to chromatin (By similarity). In addition to its role in DNA demethylation, also involved in the recruitment of the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, thereby promoting histone H2B GlcNAcylation by OGT (PubMed:23353889). Binds preferentially to DNA containing cytidine-phosphate-guanosine (CpG) dinucleotides over CpH (H=A, T, and C), hemimethylated-CpG and hemimethylated-hydroxymethyl-CpG (PubMed:29276034)","subcellular_location":"Nucleus; Cytoplasm; Chromosome","url":"https://www.uniprot.org/uniprotkb/O43151/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TET3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NONO","stoichiometry":0.2},{"gene":"PSPC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TET3","total_profiled":1310},"omim":[{"mim_id":"618798","title":"BECK-FAHRNER SYNDROME; BEFAHRS","url":"https://www.omim.org/entry/618798"},{"mim_id":"613555","title":"TET METHYLCYTOSINE DIOXYGENASE 3; TET3","url":"https://www.omim.org/entry/613555"},{"mim_id":"612839","title":"TET METHYLCYTOSINE DIOXYGENASE 2; TET2","url":"https://www.omim.org/entry/612839"},{"mim_id":"611645","title":"CXXC FINGER PROTEIN 4; CXXC4","url":"https://www.omim.org/entry/611645"},{"mim_id":"610574","title":"R-SPONDIN 3; RSPO3","url":"https://www.omim.org/entry/610574"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":18.6},{"tissue":"skin 1","ntpm":14.7}],"url":"https://www.proteinatlas.org/search/TET3"},"hgnc":{"alias_symbol":["MGC22014","hCG_40738"],"prev_symbol":[]},"alphafold":{"accession":"O43151","domains":[{"cath_id":"3.60.130.30","chopping":"830-1154_1639-1700","consensus_level":"high","plddt":93.1655,"start":830,"end":1700}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43151","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43151-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43151-F1-predicted_aligned_error_v6.png","plddt_mean":51.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TET3","jax_strain_url":"https://www.jax.org/strain/search?query=TET3"},"sequence":{"accession":"O43151","fasta_url":"https://rest.uniprot.org/uniprotkb/O43151.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43151/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43151"}},"corpus_meta":[{"pmid":"21892189","id":"PMC_21892189","title":"The role of Tet3 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\"finding\": \"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.\",\n      \"method\": \"Conditional knockout mice; immunofluorescence showing TET3 enrichment in male pronucleus; antibody staining for 5mC/5hmC in Tet3-deficient zygotes; transgene activation assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined molecular phenotype (loss of 5hmC on paternal genome), specific localization to male pronucleus, replicated by multiple subsequent labs\",\n      \"pmids\": [\"21892189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical and structural studies of CXXC domain; in vivo Xenopus loss-of-function; domain-deletion mutants; 5mC/5hmC quantification at target promoters\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of CXXC domain, in vitro enzymatic assay, mutagenesis of catalytic domain and CXXC domain, in vivo developmental phenotype\",\n      \"pmids\": [\"23217707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Affinity purification of FLAG-TET3 followed by mass spectrometry; co-immunoprecipitation with deletion mutants; chromatin fractionation; OGT stability assay\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with deletion mapping, MS identification of OGT, functional chromatin localization assay; single lab\",\n      \"pmids\": [\"24304661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; ChIP; GlcNAcylation assays; SET1/COMPASS integrity assays; Tet2 knockout mouse bone marrow tissue analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP co-localization, functional GlcNAcylation assay, SET1/COMPASS integrity, validated in KO mouse tissue; multiple orthogonal methods\",\n      \"pmids\": [\"23353889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assay; co-immunoprecipitation; enzymatic activity assay; genome-wide PGC7 binding analysis; methylation analysis at imprinting loci\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding and enzymatic suppression assay, co-IP in vivo, functional methylation readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24322296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Alternative transcript identification; in vitro DNA binding assay; in vivo 5mC hydroxylation assay; co-immunoprecipitation for Tet3-Cxxc4 interaction\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding assay, in vivo hydroxylation, Co-IP for partner interaction; single lab\",\n      \"pmids\": [\"23690950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-scale bisulfite sequencing of Tet3-depleted and DNA replication-inhibited zygotes; SNP-based allele discrimination; comparison of paternal and maternal methylation profiles\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genome-wide bisulfite sequencing in genetic KO combined with pharmacological replication inhibition, allele-resolved; multiple labs replicated Tet3's role\",\n      \"pmids\": [\"25280220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Optimized bisulfite sequencing of control and TET3-deficient zygotes; SNP-based paternal allele analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — genome-wide bisulfite sequencing with genetic KO, allele-resolved; single lab but comprehensive genomic coverage\",\n      \"pmids\": [\"25497087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse kidney fibrosis model with BMP7 administration; siRNA knockdown of Tet3; 5hmC analysis at Rasal1 promoter; fibrosis markers\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA) with defined molecular phenotype at specific locus; in vivo model; single lab\",\n      \"pmids\": [\"24480825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic rescue experiments; paternal pronucleus reconstruction bypassing 5mC oxidation; genome-scale DNA methylation analysis; heterozygous crosses\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genome-scale methylation analysis, genetic rescue with pronucleus reconstruction, multiple cross combinations; single lab but rigorous design with internal controls\",\n      \"pmids\": [\"25640176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown; Tet3 overexpression; electrophysiology in hippocampal neurons; surface GluR1 quantification; BER inhibition; RNA-seq\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional manipulation (KD and OE), electrophysiology, surface receptor quantification, BER pathway inhibition, RNA-seq; multiple orthogonal methods\",\n      \"pmids\": [\"25915473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional knockout in oocytes; immunofluorescence for TET3 localization; 5mC/5hmC staining of both pronuclei; neonatal viability analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined phenotype, direct localization imaging; single lab\",\n      \"pmids\": [\"26507142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure determination; in vitro DNA binding assays with different cytosine modifications; ChIP-seq in neuronal cells; isoform characterization\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, in vitro binding affinity measurements, genome-wide ChIP-seq in neuronal cells; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26774490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"TET3 deletion; overexpression of catalytic-dead mutant; co-immunoprecipitation of TET3 with HDAC1 and SIN3A; ChIP at Ifnb1 promoter; antiviral response assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic-dead mutant establishing non-catalytic function, Co-IP of HDAC1/SIN3A, ChIP at target promoter; single lab\",\n      \"pmids\": [\"27425624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"ATR kinase assay with TET3 as substrate; TET3 expression modulation; 5hmC level measurement after DNA damage; DNA repair and cell death assays\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified TET3 as ATR substrate, functional consequences of TET3 modulation on DDR; single lab\",\n      \"pmids\": [\"28325772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, functional transcriptional assays, catalytic-dead mutant; single lab\",\n      \"pmids\": [\"28716910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at specific promoters, bisulfite sequencing, KD with defined phenotype in vivo and in vitro; single lab\",\n      \"pmids\": [\"32023451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Tet3 conditional knockout in adult NSCs; allele-specific binding assay at Snrpn locus; neurosphere and differentiation assays; BMP2 rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined differentiation phenotype, allele-specific binding, identification of downstream effector; single lab\",\n      \"pmids\": [\"30979904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay establishing CDK5 as TET3 kinase, phospho-mutant in vivo, 5hmC mapping, H2A.Z ChIP, functional neuronal differentiation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31807777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional inducible Tet3 KO in adult neurons (Camk2a-CreERT2); behavioral assays; RNA-seq of hippocampal subregions; dendritic spine morphology analysis\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined behavioral and transcriptomic phenotype; single lab\",\n      \"pmids\": [\"32103150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of Tet3-GDH; subcellular fractionation; nuclear αKG measurement; Tet3 activity assay in presence/absence of GDH; neuronal activation experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing Tet3-GDH interaction, nuclear localization of GDH, functional stimulation of Tet3 activity; single lab\",\n      \"pmids\": [\"34215750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse hyperglycemia model; oocyte TET3 conditional KO; bisulfite sequencing of Gck and other loci from zygote to adult; insulin secretion assays; mRNA rescue injection\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic KO, mRNA rescue, bisulfite sequencing across development, functional metabolic phenotype; multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"35585240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR conditional KO, ChIP at specific promoter, 5hmC modification assay, leptin signaling link, validated in human cells; multiple orthogonal methods\",\n      \"pmids\": [\"36189793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing complex, in vitro phosphorylation assay, muscle-specific KO with functional metabolic phenotype; single lab\",\n      \"pmids\": [\"38216792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"International journal of radiation oncology, biology, physics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, functional stability assay, site-specific lysine identification; single lab\",\n      \"pmids\": [\"37244630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — catalytic-mutant vs. full KO genetic dissection, genome-wide bisulfite sequencing, RNA-seq; single lab\",\n      \"pmids\": [\"38580843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Myeloid-specific Tet3 ablation in mice; Bobcat339 treatment; VHL dependency assay; let-7 miRNA measurement; macrophage survival assays; endometriosis mouse model\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — myeloid-specific KO and pharmacological degradation, VHL-dependent degradation mechanism, let-7 feedback assay; single lab\",\n      \"pmids\": [\"39141428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Patient variant identification; catalytic activity assay for missense variants; clinical phenotyping of 11 cases from 8 families\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional catalytic assay for human variants, clinical genetics; single study but multiple independent families\",\n      \"pmids\": [\"31928709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide DNA methylation profiling (array) of whole blood from TET3-deficient patients; episignature validation against 46 other disorders; correlation with DNMT1-activating mutations\",\n      \"journal\": \"NPJ genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide methylation in human patients with defined TET3 variants, functional validation; single study\",\n      \"pmids\": [\"34750377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP for TET3 binding at Avp locus; 5hmC immunoprecipitation; TET inhibitor (IQD) treatment; qRT-PCR for Avp expression\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing TET3 binding, 5hmC measurement, pharmacological inhibition confirming TET3 dependence; single lab\",\n      \"pmids\": [\"28842817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for STAT3 at TET3 promoter, 5hmC ChIP at downstream targets, TET3 KD with in vivo phenotype; single lab\",\n      \"pmids\": [\"31819166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Inducible Tet3 knockdown in NPCs; RNA-seq; genome-scale DNA methylation (RRBS); OCT4 immunostaining; aggregate formation assay\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible KD, genome-scale methylation, transcriptomic profiling; single lab\",\n      \"pmids\": [\"31646359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Bmal1 deletion in neurons; in vitro and in vivo neurite outgrowth assays; 5hmC profiling (DhMR analysis); Tet3 expression measurement; circadian 5hmC oscillation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, genome-wide 5hmC profiling, functional axon growth assay, circadian oscillation measurement; single lab\",\n      \"pmids\": [\"37620297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — WGBS, Co-IP of transcription factor-TET3, ChIP of TET3 at specific loci, functional adipogenic assays in vitro and in vivo; multiple orthogonal methods\",\n      \"pmids\": [\"35788760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TET3 recruitment to DSBs, HR/NHEJ pathway shift assay, KO and OE functional experiments; single lab\",\n      \"pmids\": [\"39192299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TET3 is a methylcytosine dioxygenase that converts 5mC to 5hmC (and further oxidized derivatives) via an α-ketoglutarate-dependent mechanism; it is the predominant TET enzyme in oocytes, zygotes, and mature neurons, where it drives paternal (and to a lesser extent maternal) genome demethylation coupled to DNA replication, with its genomic targeting mediated by an intrinsic CXXC domain that preferentially binds 5-carboxylcytosine. Beyond its catalytic role, TET3 acts as a scaffold: it recruits OGT to chromatin (promoting H3K4me3 via SET1/COMPASS), interacts with HDAC1/SIN3A to suppress IFN-β independently of demethylation, stabilizes thyroid hormone receptors on chromatin, is recruited to DNA double-strand breaks to promote homologous recombination repair, and is phosphorylated by CDK5 and SUMOylated by SUMO1 to modulate its activity and stability. In neurons, TET3 is a synaptic activity sensor that controls surface GluR1 levels and homeostatic plasticity, and its nuclear α-ketoglutarate supply is maintained by a direct interaction with glutamate dehydrogenase redirected from mitochondria. In metabolic tissues, TET3 destabilizes PGC-1α in skeletal muscle to promote insulin resistance, and in AGRP neurons it associates with the Agrp promoter in response to leptin to restrict feeding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. 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 [#0, #6, #11, #7]; 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 [#21]. 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 [#1, #12, #5]. Catalytic activity is governed by interacting partners and post-translational modification: PGC7/Stella suppresses TET3 to protect imprints [#4], CDK5 phosphorylates the catalytic domain to retune its activity during neuronal differentiation [#18], SUMO1 stabilizes the protein [#24], and a nuclear-redirected glutamate dehydrogenase supplies α-ketoglutarate on-site to fuel demethylation in activated neurons [#20]. Beyond catalysis, TET3 functions as a chromatin scaffold—recruiting and stabilizing OGT to promote HCF1 GlcNAcylation and SET1/COMPASS-dependent H3K4me3 [#2, #3], engaging HDAC1/SIN3A to repress IFN-β independently of demethylation [#13], and stabilizing thyroid hormone receptors on chromatin [#15]. In neurons TET3 acts as a synaptic-activity sensor coupling 5mC oxidation and base-excision repair to surface GluR1 levels and homeostatic plasticity [#10], and it is recruited to DNA double-strand breaks to favor homologous recombination repair [#34, #14]. 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 [#22], destabilizing PGC-1α to promote muscle insulin resistance [#23], and driving adipogenesis through C/EBPδ-directed demethylation [#33]. Catalytic-domain missense variants cause a Mendelian neurodevelopmental disorder (TET3 deficiency/Beck-Fahrner syndrome) marked by a genome-wide hypermethylation episignature [#27, #28].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that TET3 is the enzyme responsible for active oxidative reprogramming of the paternal genome at fertilization, answering how zygotic DNA demethylation is initiated.\",\n      \"evidence\": \"Conditional KO mice with immunofluorescence for pronuclear localization and 5mC/5hmC staining in Tet3-deficient zygotes\",\n      \"pmids\": [\"21892189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve genome-wide vs locus-specific demethylation contribution\", \"Mechanism of pronuclear targeting unaddressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"CXXC domain structural/biochemical studies plus Xenopus loss-of-function and domain-deletion mutants with promoter 5mC/5hmC readouts\",\n      \"pmids\": [\"23217707\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian CXXC isoform usage not fully resolved here\", \"Direct genomic binding map absent\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a non-catalytic scaffolding axis whereby TET3 binds and stabilizes OGT on chromatin to drive HCF1 GlcNAcylation and SET1/COMPASS-dependent H3K4me3.\",\n      \"evidence\": \"Affinity purification/MS, reciprocal Co-IP with deletion mapping, ChIP co-localization, GlcNAcylation and COMPASS integrity assays\",\n      \"pmids\": [\"24304661\", \"23353889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this axis operates in zygotic reprogramming untested\", \"Direct chromatin recruitment determinants unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed TET3 activity is negatively regulated by PGC7/Stella, explaining how imprinted loci escape oxidative demethylation.\",\n      \"evidence\": \"In vitro binding, Co-IP, enzymatic suppression assays and methylation analysis at imprinting loci\",\n      \"pmids\": [\"24322296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of inhibition unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genome-scale bisulfite sequencing of Tet3-depleted and replication-inhibited zygotes with allele resolution\",\n      \"pmids\": [\"25280220\", \"25497087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weighting of active vs passive demethylation per locus class incomplete\", \"Mechanism of CpG-island protection unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that the maternal Tet3 knockout developmental phenotype reflects haploinsufficiency rather than failed paternal 5mC oxidation, separating gene dosage from catalytic reprogramming.\",\n      \"evidence\": \"Genetic rescue with paternal pronucleus reconstruction and genome-scale methylation analysis across crosses\",\n      \"pmids\": [\"25640176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which dosage-sensitive TET3 functions cause sublethality unidentified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified TET3 as a synaptic-activity sensor controlling excitatory transmission through 5mC oxidation, base-excision repair, and surface GluR1 regulation.\",\n      \"evidence\": \"Bidirectional shRNA knockdown/overexpression with electrophysiology, surface receptor quantification and BER inhibition in hippocampal neurons\",\n      \"pmids\": [\"25915473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct genomic targets controlling GluR1 not mapped\", \"Link between BER and receptor trafficking mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Crystal structure of CXXC bound to 5caC-DNA, in vitro binding by modification state, and neuronal ChIP-seq\",\n      \"pmids\": [\"26774490\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of 5caC preference in vivo unclear\", \"Isoform-specific targeting in non-neuronal cells untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a demethylation-independent immunoregulatory function in which TET3's catalytic domain recruits HDAC1/SIN3A to repress IFN-β.\",\n      \"evidence\": \"Catalytic-dead mutant rescue, Co-IP of HDAC1/SIN3A and ChIP at the Ifnb1 promoter\",\n      \"pmids\": [\"27425624\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How catalytic domain selects the Ifnb1 locus unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected TET3 to the DNA damage response by showing it is an ATR substrate whose 5mC oxidation supports efficient repair.\",\n      \"evidence\": \"ATR kinase assay with TET3 as substrate plus expression modulation and repair/cell-death assays\",\n      \"pmids\": [\"28325772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphosites and their functional effect not mapped\", \"Direct recruitment to lesions not shown here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a non-catalytic transcriptional co-regulator role in which TET3 stabilizes thyroid hormone and other nuclear receptors on chromatin.\",\n      \"evidence\": \"Co-IP, ChIP for receptor chromatin retention, reporter assays and catalytic-dead mutant retaining interaction\",\n      \"pmids\": [\"28716910\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Generality across nuclear receptor superfamily incompletely defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed non-catalytic, allele-specific TET3 binding maintains neural stem cell identity by repressing the imprinted Snrpn-BMP2 axis and preventing premature astrocytic differentiation.\",\n      \"evidence\": \"Conditional KO and inducible knockdown in NSCs/NPCs with allele-specific binding, methylation profiling and BMP2 rescue\",\n      \"pmids\": [\"30979904\", \"31646359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of allele-specific recognition unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified CDK5 phosphorylation of the TET3 catalytic domain as a switch that retunes dioxygenase activity, H2A.Z association and neuronal gene activation.\",\n      \"evidence\": \"In vitro CDK5 kinase assay, phospho-mutant expression in triple-KO ESCs, 5hmC mapping and H2A.Z ChIP during differentiation\",\n      \"pmids\": [\"31807777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of phosphosites untested\", \"How phosphorylation alters H2A.Z binding mechanistically unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established TET3 as a causal gene for a Mendelian neurodevelopmental disorder, linking catalytic loss-of-function to human disease and behavior.\",\n      \"evidence\": \"Patient missense variant identification with catalytic activity assays, clinical phenotyping and adult-neuron conditional KO behavioral/transcriptomic analysis\",\n      \"pmids\": [\"31928709\", \"32103150\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single clinical cohort\", \"Molecular targets driving behavioral phenotypes not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, nuclear αKG measurement and TET3 activity assays with/without GDH\",\n      \"pmids\": [\"34215750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of GDH nuclear redirection unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided a clinical functional biomarker by defining a genome-wide hypermethylation episignature for TET3 catalytic loss-of-function in patient blood.\",\n      \"evidence\": \"Genome-wide methylation array profiling of TET3-deficient patients with validation against other disorders\",\n      \"pmids\": [\"34750377\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study\", \"Tissue-specificity of the episignature not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Hyperglycemia model, oocyte conditional KO, developmental bisulfite sequencing, insulin secretion assays and mRNA rescue\",\n      \"pmids\": [\"35585240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human translation limited to expression correlation\", \"Other affected loci beyond Gck incompletely cataloged\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"36189793\", \"38216792\", \"35788760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these roles share a common recruitment logic unclear\", \"Reconciling activating vs repressive outcomes mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated TET3 in DNA double-strand break repair pathway choice, showing recruitment to breaks promotes homologous recombination and restrains fibroblast proliferation.\",\n      \"evidence\": \"TET3 recruitment to H2O2-induced DSBs, HR/NHEJ pathway assays and KO/overexpression in cardiac fibrosis models\",\n      \"pmids\": [\"39192299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether recruitment is catalytic or scaffolding not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Catalytic-mutant vs full-knockout ESC differentiation with WGBS and RNA-seq\",\n      \"pmids\": [\"38580843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular basis of mesoderm suppression unidentified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 6, 12, 18, 27]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 18]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 12, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [13, 15, 22, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 11, 24]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 3, 12, 18]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 3, 12, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 13, 15, 22, 33]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [14, 34]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 25, 33]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 18, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [21, 22, 23, 33]}\n    ],\n    \"complexes\": [\"SIN3A/HDAC1 corepressor complex\"],\n    \"partners\": [\"OGT\", \"HDAC1\", \"SIN3A\", \"PGC7/DPPA3\", \"PPARGC1A\", \"CEBPD\", \"GLUD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}