{"gene":"TET2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2013,"finding":"Crystal structure of human TET2 bound to methylated DNA at 2.02 Å resolution revealed that two zinc fingers bring the Cys-rich and DSBH domains together to form a compact catalytic domain; the Cys-rich domain stabilizes DNA above the DSBH core; TET2 specifically recognizes CpG dinucleotide with 5mC inserted into the catalytic cavity with the methyl group oriented toward catalytic Fe(II); the catalytic cavity accommodates 5mC derivatives for further iterative oxidation.","method":"X-ray crystallography (2.02 Å), active-site mutagenesis of Fe(II)/NOG-chelating, DNA-interacting, and zinc-chelating residues","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional mutagenesis validation in a single rigorous study","pmids":["24315485"],"is_preprint":false},{"year":2010,"finding":"IDH1/2 neomorphic mutations produce 2-hydroxyglutarate (2HG), which inhibits TET2 catalytic function in cells; expression of 2HG-producing IDH alleles impairs TET2-mediated DNA hydroxymethylation and induces global DNA hypermethylation phenotypically similar to TET2 loss-of-function; IDH1/2 mutations and TET2 mutations are mutually exclusive in AML and produce overlapping epigenetic defects.","method":"Mutational and epigenetic profiling of AML patient cohort; cellular expression of mutant IDH alleles with measurement of TET2 catalytic activity; genetic epistasis (mutual exclusivity analysis)","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (patient cohort genetics, cellular enzymatic assay, epigenetic profiling), replicated conceptually across multiple labs","pmids":["21130701"],"is_preprint":false},{"year":2013,"finding":"TET2 and TET3 directly interact with O-GlcNAc transferase (OGT); TET2/3 promote OGT enzymatic activity without OGT influencing TET2/3 hydroxymethylation activity; TET2/3-OGT co-localize at active promoters enriched for H3K4me3; reduction of TET2/3 or OGT decreases H3K4me3 and transcription; HCF1 (a SET1/COMPASS component) is a specific GlcNAcylation target of TET2/3-OGT and its modification is important for SET1/COMPASS integrity; Tet2 knockout mouse bone marrow shows decreased global GlcNAcylation and H3K4me3.","method":"Co-immunoprecipitation, ChIP, enzymatic activity assays, Tet2 knockout mouse bone marrow analysis, mass spectrometry","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods, validated in knockout mouse model","pmids":["23353889"],"is_preprint":false},{"year":2015,"finding":"TET2 selectively represses IL-6 transcription during inflammation resolution in innate myeloid cells independently of its DNA methylation/hydroxymethylation enzymatic activity; IκBζ mediates specific targeting of TET2 to the Il6 promoter; TET2 recruits HDAC2 to repress IL-6 transcription via histone deacetylation.","method":"Tet2-deficient mouse model (endotoxin shock and colitis), ChIP, reporter assays, Co-immunoprecipitation of TET2 with HDAC2, catalytically inactive TET2 rescue experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, KO mouse phenotype, catalytic mutant rescue), single lab but rigorous","pmids":["26287468"],"is_preprint":false},{"year":2018,"finding":"TET2 promotes infection-induced myelopoiesis through mRNA oxidation in an enzymatic-activity-dependent manner; TET2 mediates oxidation of 5-methylcytosine (m5C) in mRNA; TET2 deficiency leads to transcriptome-wide accumulation of m5C including in the 3'UTR of Socs3 mRNA, which influences double-stranded RNA formation for ADAR1 binding; TET2 represses Socs3 expression through ADAR1 (RNA editing-independent), reducing Socs3 mRNA stability and thereby relieving JAK-STAT pathway suppression to promote myelopoiesis.","method":"Tet2 knockout mouse models (sepsis and parasite infection), RNA m5C sequencing, mRNA stability assays, ADAR1 knockdown epistasis experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, m5C mapping, genetic epistasis in vivo), rigorous mechanistic dissection","pmids":["29364877"],"is_preprint":false},{"year":2019,"finding":"JAK2 phosphorylates TET2 at tyrosines Y1939 and Y1964 in response to hematopoietic cytokines, activating TET2 enzymatic activity; phosphorylated TET2 interacts with the erythroid transcription factor KLF1, with this interaction enhanced by erythropoietin; activating JAK2V617F mutation increases TET2 activity, cytosine hydroxymethylation, and genome-wide loss of cytosine methylation.","method":"Phospho-specific antibodies, Co-immunoprecipitation, in vitro kinase assays, JAK2V617F patient samples and mouse models, genome-wide methylation analysis","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro kinase assay, Co-IP, patient samples and mouse models, multiple orthogonal methods","pmids":["30944118"],"is_preprint":false},{"year":2019,"finding":"IFNγ stimulates STAT1 to bind TET2 and recruit TET2 to hydroxymethylate chemokine and PD-L1 gene loci; TET2 mediates IFNγ-JAK-STAT signaling to control chemokine expression, PD-L1 expression, and lymphocyte infiltration; deletion of Tet2 in murine tumor cells reduced chemokine expression and tumor-infiltrating lymphocytes.","method":"Co-immunoprecipitation (STAT1-TET2), ChIP, Tet2 conditional knockout in tumor cells, hMeDIP, in vivo tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP, conditional KO with defined phenotypic readouts, multiple orthogonal methods","pmids":["31310587"],"is_preprint":false},{"year":2019,"finding":"AMPK phosphorylates TET2 at serine S97, enhancing TET2 stability by promoting its binding to 14-3-3β; AMPK ablation results in decreased global 5-hmC levels and severe myogenic differentiation defects; phospho-mimicking TET2-S97E partially rescues differentiation defects in AMPK-null cells.","method":"In vitro kinase assay, Co-immunoprecipitation, CRISPR/Cas9 knockout, genome-wide 5-hmC mapping, AMPK-null C2C12 cells, phosphomimetic rescue","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay, Co-IP, CRISPR KO with functional rescue by phosphomimetic mutant","pmids":["31164154"],"is_preprint":false},{"year":2017,"finding":"TET2-deficient macrophages exhibit increased NLRP3 inflammasome-mediated IL-1β secretion; partial bone marrow reconstitution with TET2-deficient cells is sufficient for clonal expansion and marked increase in atherosclerotic plaque size in Ldlr-/- mice; NLRP3 inhibition shows greater atheroprotective activity in TET2-deficient chimeric mice.","method":"Bone marrow transplantation (chimeric mice), NLRP3 inhibitor treatment, IL-1β measurement, plaque size quantification","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined cellular phenotype with genetic KO and pharmacological inhibitor, replicated across multiple experimental approaches","pmids":["28104796"],"is_preprint":false},{"year":2020,"finding":"TET2 chemically modifies tRNAs by depositing the 5-hydroxymethylcytosine (hm5C) modification; TET2 is necessary and sufficient for hm5C deposition on tRNA as shown by mass spectrometry; Tet2 knockout in mESCs affects levels of small noncoding RNAs (tRNA fragments) enriched by hm5C immunoprecipitation.","method":"Stringent affinity-tag purification and crosslinking RNA immunoprecipitation-sequencing from endogenously-tagged Tet2, mass spectrometry, Tet2 knockout mESCs, hm5C immunoprecipitation","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mass spectrometry demonstrating necessity and sufficiency, endogenous tagging, multiple orthogonal methods in single study","pmids":["33230319"],"is_preprint":false},{"year":2024,"finding":"TET2 oxidizes m5C on chromatin-associated retrotransposon RNA; MBD6 protein recognizes retrotransposon RNA m5C and guides deubiquitination of H2AK119ub to promote open chromatin; TET2 oxidizes m5C and antagonizes MBD6-dependent H2AK119ub deubiquitination; TET2 depletion leads to globally decreased H2AK119ub, more open chromatin, and increased transcription; MBD6 depletion selectively blocks proliferation of TET2-mutant leukemic cells.","method":"RNA m5C mapping, H2AK119ub ChIP-seq, MBD6 Co-IP, CRISPR knockout of MBD6 in TET2-mutant leukemic cells, mouse models of TET2-loss hematopoiesis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (RNA m5C mapping, ChIP-seq, Co-IP, genetic rescue), mechanistic dissection with therapeutic validation","pmids":["39358506"],"is_preprint":false},{"year":2023,"finding":"TET2 deficiency in AML increases expression of TSPAN13 through accumulation of m5C modification on TSPAN13 mRNA; YBX1 specifically recognizes m5C-modified TSPAN13 mRNA and increases its stability and expression; increased TSPAN13 activates CXCR4/CXCL12 signaling, leading to increased homing/migration of leukemia stem cells into bone marrow niche, enhancing self-renewal.","method":"m5C RNA sequencing, RIP assays (YBX1), Co-IP, CXCR4/CXCL12 signaling assays, multiple AML mouse models, human LSC transplantation","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA m5C sequencing, Co-IP, multiple AML models with mechanistic pathway dissection","pmids":["37541212"],"is_preprint":false},{"year":2021,"finding":"PROSER1 mediates the interaction between OGT and TET2, promoting TET2 O-GlcNAcylation and protein stability; loss of PROSER1 results in lower enrichment of TET2 at enhancers and CpG islands, with concomitant increase in DNA methylation; PROSER1, UTX, TET1/2, and OGT co-localize on enhancers and CpG islands genome-wide.","method":"Co-immunoprecipitation, genome-wide ChIP-seq, DNA methylation analysis, PROSER1 knockout cells, O-GlcNAcylation assays","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, KO with defined molecular phenotype, multiple orthogonal methods in single lab","pmids":["34667079"],"is_preprint":false},{"year":2018,"finding":"TET2 disruption in CAR T cells (via lentiviral integration) produces an epigenetic profile consistent with altered T cell differentiation and a central memory phenotype at peak expansion; experimental knockdown of TET2 recapitulates the potency-enhancing effect on CAR T cell expansion and anti-tumor activity.","method":"Clinical case analysis, lentiviral integration site mapping, ATAC-seq/epigenetic profiling, experimental TET2 knockdown in CAR T cells","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clinical observation validated by experimental TET2 knockdown with defined epigenetic and functional phenotype","pmids":["29849141"],"is_preprint":false},{"year":2023,"finding":"TET2 loss enables antigen-independent CAR T cell clonal expansion; these clonal proliferations require biallelic TET2 disruption and sustained expression of BATF3 to drive a MYC-dependent proliferative program; TET2 acts as a guardian against BATF3-induced CAR T cell proliferation and genomic instability.","method":"Genetic TET2 disruption (biallelic vs monoallelic) in CAR T cells, BATF3 overexpression epistasis, transcriptomic analysis, in vivo tumor models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (biallelic vs monoallelic), BATF3 epistasis, multiple orthogonal methods","pmids":["36755094"],"is_preprint":false},{"year":2018,"finding":"PML physically binds TET2 via the PML C-terminal domain and recruits TET2 to PML-positive nuclear bodies; this interaction promotes 5-hmC formation in response to chemotherapeutic agents (doxorubicin); the PML-RARA t(15;17) fusion disrupts PML-TET2 interaction; knockout of PML abolishes doxorubicin-promoted DNA modification.","method":"SILAC-MS interactome, Co-immunoprecipitation, PML knockout cells, 5-hmC dot-blot assay, domain-mapping experiments","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — SILAC-MS, Co-IP with domain mapping, KO validation, multiple orthogonal methods in single study","pmids":["29735542"],"is_preprint":false},{"year":2016,"finding":"TET2 regulates mast cell differentiation through its catalytic (hydroxymethylation) activity affecting gene expression and enhancer 5-hmC deposition, while TET2 control of mast cell proliferation is strictly dependent on TET2 protein expression and cannot be rescued by catalytically inactive TET2.","method":"Tet2 knockout mouse-derived mast cells, re-expression of wild-type vs catalytically inactive TET2, genome-wide 5-hmC mapping, gene expression analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — catalytic mutant rescue separating enzymatic vs non-enzymatic functions, genome-wide 5-hmC mapping, clean KO phenotype","pmids":["27160912"],"is_preprint":false},{"year":2019,"finding":"TET2 binds NANOG in embryonic stem cells; TET2 protein expression is restricted to the naïve pluripotent state; TET2-negative ESCs lose the ability to form undifferentiated ESC colonies.","method":"CRISPR/Cas9 endogenous epitope-tagging of Tet2, Co-immunoprecipitation (TET2-NANOG), FACS sorting of TET2-reporter ESCs with colony-forming assay","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and endogenous tagging, single lab, NANOG interaction not fully characterized mechanistically","pmids":["31582397"],"is_preprint":false},{"year":2018,"finding":"TET2 interacts with PPARγ and is required for PPARγ binding to target loci upon activation with Rosiglitazone; TET2 is necessary for Rosiglitazone-dependent gene activation of PPARγ targets with concomitant DNA demethylation at promoter regions; TET2 gain-of-function promotes insulin sensitivity in adipocytes.","method":"Co-immunoprecipitation (TET2-PPARγ), ChIP-PCR, DNA methylation analysis, siRNA knockdown/overexpression, insulin-stimulated glucose uptake assay","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, ChIP, functional assays, single lab with multiple methods but no structural validation","pmids":["30193945"],"is_preprint":false},{"year":2022,"finding":"TET2 deficiency in macrophages leads to increased JNK1 phosphorylation through increased promoter methylation and decreased expression of the JNK-inactivating phosphatase DUSP10; increased JNK1 signaling leads to NLRP3 deubiquitylation and activation by the deubiquitinase BRCC3; targeted editing of DUSP10 promoter methylation abolished cholesterol-induced inflammasome activation in Tet2-deficient macrophages.","method":"Tet2-deficient murine and human ESC-derived isogenic macrophages, Dusp10 promoter methylation editing (active Tet1-deadCas9), BRCC3 inhibitor (holomycin), Abro1 hematopoietic KO epistasis, NLRP3 ubiquitylation assay","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches including promoter editing, pharmacological inhibition, genetic epistasis, and human cell validation","pmids":["37781816"],"is_preprint":false},{"year":2023,"finding":"IL-1 receptor 1 (IL-1R1)-dependent signaling drives expansion of Tet2+/- hematopoietic stem and progenitor cells during aging; IL-1α-treated Tet2+/- HSCs show increased DNA replication and self-renewal transcriptomic signatures; genetic deletion of IL-1R1 in Tet2+/- HSPCs or pharmacologic inhibition of IL-1 signaling impairs Tet2+/- clonal expansion.","method":"Bone marrow transplantation mouse models, genetic mosaicism model (Tet2+/flox), IL-1 administration, IL-1R1 genetic deletion epistasis, IL-1 pharmacological inhibition","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (IL-1R1 deletion), pharmacological validation, multiple mouse model approaches","pmids":["36379023"],"is_preprint":false},{"year":2018,"finding":"ETV2 directly interacts with TET2 (and TET1); ETV2-TET1/TET2 complexes demethylate the Robo4 proximal promoter and induce endothelial cell-specific Robo4 expression during iPS cell differentiation into endothelial cells.","method":"Co-immunoprecipitation (ETV2-TET2), adenoviral overexpression of ETV2-TET1/TET2 in non-endothelial cells, reporter assay, bisulfite sequencing of Robo4 promoter","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, functional demethylation assay with overexpression system, single lab","pmids":["29618782"],"is_preprint":false},{"year":2019,"finding":"TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1 promoters in mammary cells; Tet2 deletion impairs mammary luminal lineage commitment and reduces ERα expression, conferring tamoxifen resistance in vivo.","method":"Mammary-specific Tet2 conditional KO mouse, Co-immunoprecipitation (TET2-FOXP1), ChIP, bisulfite sequencing of ESR1/GATA3/FOXA1 promoters, Tet2-PyMT mammary tumor model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, bisulfite sequencing, conditional KO with defined in vivo phenotype, multiple orthogonal methods","pmids":["32934200"],"is_preprint":false},{"year":2023,"finding":"TET2 regulates the spatial redistribution of H3K9me3-marked heterochromatin; TET2 deficiency in HSPCs retains perinuclear distribution of heterochromatin and leads to upregulation of endogenous retroviruses (ERVs) and interferon-stimulated genes (ISGs), contributing to functional decline of aged HSPCs.","method":"TET2-deficient HSPCs, genome-wide H3K9me3 ChIP-seq, 3D nuclear imaging, reverse transcriptase inhibitor treatment, single-cell RNA-seq","journal":"Nature aging","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP-seq, 3D imaging, pharmacological rescue, single lab without full mechanistic reconstitution","pmids":["37884767"],"is_preprint":false},{"year":2023,"finding":"Elevated CEBPA levels (driven by CEBPA N-terminal mutations) recruit TET2 to the Gata2 distal hematopoietic enhancer, increasing Gata2 expression; concurrent TET2 loss in CEBPA double-mutant AML increases Gata2 promoter methylation to rebalance GATA2 levels, conferring competitive advantage.","method":"CEBPA-TET2 co-mutated patient transcriptomic/epigenomic analysis, ChIP-seq, DNA methylation analysis, mouse models of CEBPA-TET2 co-mutation, demethylating agent treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq showing TET2 recruitment, epigenomic analysis, patient data and mouse models, multiple orthogonal methods","pmids":["37794021"],"is_preprint":false},{"year":2023,"finding":"TET2 is enriched at active enhancers and promoters in embryonic stem cells where it demethylates DNA; TET2 partners with the histone deacetylase component Sin3a, co-localizing at promoters and active enhancers; TET2 deficiency diminishes Sin3a at these regions; combined loss of Tet1/2 (but not their catalytic activities) reduces Sin3a at active enhancers.","method":"Tet2 catalytic mutant and knockout ESCs, ChIP-seq, Co-immunoprecipitation (TET2-Sin3a), mass spectrometry, Tet1/2 double KO ESCs","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, catalytic mutant dissection, multiple ESC genetic models","pmids":["37456851"],"is_preprint":false},{"year":2024,"finding":"TET2 is poly-ubiquitinated by E3 ligase CUL7-FBXW11 and degraded via proteasome in EGFR-TKI resistant NSCLC cells; MEK1 phosphorylates TET2 at Ser1107, stabilizing it, while MEK1 inactivation enhances CUL7-FBXW11 recruitment and TET2 proteasomal degradation; TET2 loss upregulates TNF/NF-κB signaling conferring EGFR-TKI resistance.","method":"Co-immunoprecipitation (TET2-CUL7-FBXW11, TET2-MEK1), ubiquitination assay, phospho-site mutagenesis, NF-κB inhibition in vitro and in vivo","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, phospho-mutagenesis, in vitro and in vivo validation, single lab","pmids":["38461173"],"is_preprint":false},{"year":2024,"finding":"TET2 promotes CXCL5 expression through STAT3 binding to the CXCL5 promoter, driving neutrophil infiltration; TET2-mediated DNA demethylation is elevated during lung adeno-to-squamous transition (AST) and Tet2 is required for squamous transition.","method":"Tet2 conditional KO in KrasG12D/Lkb1 mouse model, STAT3 ChIP, CXCL5 promoter methylation analysis, neutrophil depletion experiments","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — ChIP, genetic KO in vivo model, single lab","pmids":["38805014"],"is_preprint":false},{"year":2023,"finding":"TET2 functions as an mRNA m5C demethylase (eraser); TET2 deficiency leads to accumulation of m5C in mRNAs of urea cycle enzymes; YBX1-HuR binding is abolished by TET2-mediated m5C oxidation, promoting decay of urea cycle enzyme mRNAs; loss of TET2 increases arginine production through the urea cycle, activating mTORC1 signaling and promoting cell growth.","method":"mRNA m5C sequencing (MeRIP-seq), RIP assays (YBX1-HuR), urea cycle metabolite measurement, mTORC1 activity assays, TET2 KO tumor cell lines","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq, RIP assays, metabolic measurements, multiple cell line models, single lab","pmids":["37550284"],"is_preprint":false},{"year":2022,"finding":"Vitamin D receptor (VDR) and JAK2-phosphorylated STAT3 interact with TET2 to form a complex; JAK2-mediated STAT3 phosphorylation is specific to vitamin D stimulation; VDR-STAT3-TET2 complex drives DNA demethylation and transcriptional activation at VDR binding sites during tolerogenic DC differentiation; pharmacological inhibition of JAK2 reverts vitamin D-induced tolerogenic properties.","method":"Co-immunoprecipitation (VDR-STAT3-TET2), JAK2 inhibitor treatment, genome-wide DNA methylation analysis, phospho-STAT3 analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP of triple complex, pharmacological validation, single lab","pmids":["35045292"],"is_preprint":false},{"year":2020,"finding":"Tet2 and Tet3 in B cells are required for downregulation of CD86 following chronic self-antigen exposure; Tet2/3-deficient B cells show decreased accumulation of HDAC1 and HDAC2 at the Cd86 locus; anti-CD86 blockade partially restricts aberrant T and B cell activation caused by Tet2/3 deficiency.","method":"Tet2/3 conditional B cell-specific KO mice, ChIP (HDAC1/2 at Cd86), mixed bone marrow chimeras, anti-CD86 antibody blockade","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined molecular mechanism (ChIP), functional rescue with antibody blockade, multiple experimental approaches","pmids":["32572241"],"is_preprint":false},{"year":2024,"finding":"Leptin suppresses adipocyte TET2 levels via JAK2-STAT3 signaling; TET2 interacts with C/EBPα and increases 5-hydroxymethylcytosine levels at the leptin gene promoter, thereby promoting leptin gene expression; adipocyte TET2 deficiency reduces leptin levels and improves leptin sensitivity in obese mice.","method":"Co-immunoprecipitation (TET2-C/EBPα), JAK2-STAT3 inhibition, hMeDIP at leptin promoter, adipocyte-specific Tet2 KO mice, leptin measurement","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, hMeDIP, conditional KO with defined phenotype, signaling pathway dissection, single lab","pmids":["38561362"],"is_preprint":false},{"year":2016,"finding":"TET2 binds endogenous androgen receptor (AR) and AR-coactivator proteins in prostate cancer cells; TET2 knockdown increases PSA (KLK3) expression; TET2 binding sites and 5-hydroxymethylcytosine are found proximal to KLK3; TET2 knockdown increases LNCaP cell proliferation and migration.","method":"Co-immunoprecipitation (TET2-AR), siRNA knockdown, published ChIP-seq and 5-hmC mapping, cell proliferation and migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, siRNA KD with functional readouts, relied partly on published ChIP data, single lab","pmids":["27819678"],"is_preprint":false},{"year":2024,"finding":"Tet2 deficiency in myeloid cells promotes renal macrophage infiltration, NLRP3 inflammasome activation, elevated IL-1β and IL-18, and sodium retention activating NCC and NKCC2 transporters, sensitizing mice to hypertension; NLRP3 inhibitor MCC950 reversed hypertensive state and sodium retention in Tet2-deficient chimeric mice.","method":"Bone marrow transplantation (Tet2-/- chimeras), Angiotensin II subpressor dose challenge, NLRP3 inhibitor treatment, renal transporter phosphorylation analysis, cytokine measurement","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with pharmacological rescue, defined molecular pathway (NLRP3-IL-1β-sodium transporter), multiple readouts","pmids":["39234670"],"is_preprint":false},{"year":2024,"finding":"Tet2 modulates M2 macrophage polarization by demethylating m5C in mRNAs of M2-related genes Klf4 and Rock1; Tet2 deficiency decreases mRNA m5C demethylation of Klf4 and Rock1, contributing to M2 polarization; Tet2-/- mice show increased AR severity and macrophage M2 skewing.","method":"MeRIP-qPCR (m5C on Klf4 and Rock1 mRNA), Tet2 KO mice (OVA-AR model), BMDMs from WT and Tet2-/- mice, RNA sequencing","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — MeRIP-qPCR, KO mouse model with in vitro validation, single lab","pmids":["39486186"],"is_preprint":false},{"year":2022,"finding":"TET2-mediated 5-hmC modification at the ZO-1 (tight junction) promoter region regulates ZO-1 expression in cerebral vascular endothelial cells; ROS (H2O2) decreases TET2-mediated 5-hmC at the ZO-1 promoter and reduces ZO-1 expression; Tet2 KO mice show reduced 5-hmC in endothelial cells and reduced ZO-1 expression.","method":"Tet2 KO mice, siRNA knockdown, hMeChIP-PCR at ZO-1 promoter, H2O2 treatment, BBB permeability assays","journal":"Fluids and barriers of the CNS","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — hMeChIP-PCR, KO mouse and siRNA knockdown, functional BBB assay, single lab","pmids":["36076297"],"is_preprint":false},{"year":2018,"finding":"TET2 regulates osteoclast differentiation by inhibiting BCL2 expression, which allows BECN1-dependent autophagy; TET2 knockdown increases BCL2 expression and BCL2-BECN1 binding, thereby suppressing autophagy and impairing osteoclast differentiation; siRNA knockdown of Bcl2 in Tet2-knockdown cells partially rescues autophagy and osteoclast differentiation.","method":"Tet2 siRNA knockdown, Co-IP (BCL2-BECN1), Bcl2 siRNA epistasis, autophagy assays, OVX mouse model with LV-shTet2","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP, epistasis via double knockdown, in vivo lentiviral KD, single lab","pmids":["35255774"],"is_preprint":false}],"current_model":"TET2 is an Fe(II)- and α-ketoglutarate-dependent dioxygenase that iteratively oxidizes 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives in DNA (and m5C in RNA including mRNAs, tRNAs, and retrotransposon RNAs), acting as a DNA/RNA demethylase whose activity is activated by JAK2-mediated phosphorylation (Y1939/Y1964) and AMPK-mediated phosphorylation (S97, enhancing stability via 14-3-3β binding), inhibited by 2-hydroxyglutarate (produced by mutant IDH1/2), and regulated by proteasomal degradation via CUL7-FBXW11 (counteracted by MEK1 phosphorylation); TET2 functions in multiprotein complexes—interacting with OGT to promote GlcNAcylation and H3K4me3 via SET1/COMPASS, with HDAC2 to repress IL-6 transcription independently of its catalytic activity, with STAT1 downstream of IFNγ-JAK signaling to hydroxymethylate chemokine and PD-L1 loci, with BATF3/MYC to restrain CAR T cell proliferation, and with Sin3a at active enhancers—while RNA m5C oxidation by TET2 antagonizes MBD6-dependent H2AK119ub deubiquitination to maintain chromatin compaction, collectively establishing TET2 as a multi-substrate epigenetic regulator that integrates extracellular signals with DNA/RNA methylation status to govern hematopoietic stem cell self-renewal, immune cell differentiation, and inflammatory responses."},"narrative":{"mechanistic_narrative":"TET2 is an Fe(II)- and α-ketoglutarate-dependent dioxygenase that integrates extracellular signaling with the methylation status of DNA and RNA to govern hematopoietic stem cell self-renewal, immune cell differentiation, and inflammatory responses [PMID:21130701, PMID:28104796]. Its catalytic domain, formed when two zinc fingers bring together the Cys-rich and double-stranded β-helix (DSBH) domains, recognizes CpG dinucleotides and inserts 5-methylcytosine into the catalytic cavity to position the methyl group toward catalytic Fe(II), enabling iterative oxidation of 5mC to 5-hydroxymethylcytosine and further derivatives [PMID:24315485]; this activity is blocked by 2-hydroxyglutarate produced by neomorphic IDH1/2 mutations, which phenocopies TET2 loss and is mutually exclusive with TET2 mutation in AML [PMID:21130701]. Beyond DNA, TET2 oxidizes 5-methylcytosine in mRNAs, tRNAs, and chromatin-associated retrotransposon RNA, functioning as an RNA m5C eraser that controls transcript stability and chromatin state—destabilizing Socs3, TSPAN13, and urea-cycle enzyme mRNAs through m5C readers such as ADAR1, YBX1, and HuR, and antagonizing MBD6-guided H2AK119ub deubiquitination to maintain chromatin compaction [PMID:29364877, PMID:39358506, PMID:37541212, PMID:37550284]. TET2 catalytic output is tuned by post-translational signals: JAK2 phosphorylates Y1939/Y1964 to activate the enzyme downstream of hematopoietic cytokines, AMPK phosphorylates S97 to stabilize TET2 via 14-3-3β binding, and CUL7-FBXW11-mediated ubiquitination drives proteasomal degradation that MEK1 phosphorylation opposes [PMID:30944118, PMID:31164154, PMID:38461173]. TET2 also acts within multiprotein complexes—stimulating OGT-dependent GlcNAcylation and H3K4me3 via SET1/COMPASS, partnering with Sin3a at active enhancers, and being recruited to specific loci by transcription factors and STAT proteins (STAT1, STAT3) downstream of IFNγ and other cytokines to demethylate or hydroxymethylate target genes [PMID:23353889, PMID:37456851, PMID:31310587, PMID:35045292]. A distinct, catalytically independent function recruits HDAC2 to the Il6 promoter via IκBζ to repress IL-6 during inflammation resolution, and TET2 loss broadly de-represses inflammatory programs including NLRP3 inflammasome activation [PMID:26287468, PMID:28104796]. Through these activities TET2 restrains clonal expansion of hematopoietic cells, and its loss confers selective advantages in clonal hematopoiesis, atherosclerosis, and CAR T cell proliferation [PMID:28104796, PMID:36755094, PMID:36379023].","teleology":[{"year":2010,"claim":"Established that TET2 catalytic function can be antagonized in trans, linking a metabolic oncometabolite to TET2-type epigenetic defects and uniting two AML mutation classes mechanistically.","evidence":"AML cohort genetics, cellular expression of mutant IDH alleles with catalytic activity measurement, and mutual-exclusivity epistasis","pmids":["21130701"],"confidence":"High","gaps":["Did not resolve which TET2 genomic targets drive the leukemic phenotype","2HG inhibition mechanism inferred in cells, not from purified enzyme kinetics here"]},{"year":2013,"claim":"Defined the structural basis for how TET2 recognizes 5mC within CpG context and positions it for iterative oxidation, anchoring all downstream catalytic interpretations.","evidence":"2.02 Å X-ray crystal structure of TET2 bound to methylated DNA with active-site mutagenesis","pmids":["24315485"],"confidence":"High","gaps":["Structure captured DNA substrate only; no structural insight into RNA substrate engagement","Does not address regulation by post-translational modification or partners"]},{"year":2013,"claim":"Revealed that TET2 acts non-catalytically as a scaffold coupling OGT-mediated GlcNAcylation to active chromatin, expanding its role beyond demethylation.","evidence":"Reciprocal Co-IP, ChIP, enzymatic assays, mass spectrometry of HCF1, and Tet2 knockout mouse bone marrow","pmids":["23353889"],"confidence":"High","gaps":["How TET2 enhances OGT activity at the molecular level unresolved","Relative contribution of OGT scaffolding versus DNA demethylation to H3K4me3 not separated"]},{"year":2015,"claim":"Demonstrated a catalysis-independent repressive function, showing TET2 recruits HDAC2 to silence Il6 during inflammation resolution.","evidence":"Tet2-deficient mouse inflammation models, ChIP, Co-IP, and catalytically inactive TET2 rescue","pmids":["26287468"],"confidence":"High","gaps":["Generality of IκBζ-mediated targeting to other loci unknown","Structural basis of TET2-HDAC2 interaction not defined"]},{"year":2016,"claim":"Separated TET2's catalytic and non-catalytic roles in a single lineage, showing differentiation depends on hydroxymethylation while proliferation control needs only protein presence.","evidence":"Tet2 knockout mast cells with wild-type versus catalytically inactive re-expression and genome-wide 5-hmC mapping","pmids":["27160912"],"confidence":"High","gaps":["Non-catalytic proliferation-control partners not identified","Mechanism distinguishing the two functions at specific loci unclear"]},{"year":2017,"claim":"Connected TET2 loss to a discrete inflammatory mechanism driving disease, showing TET2-deficient macrophages hyperactivate the NLRP3 inflammasome to accelerate atherosclerosis.","evidence":"Bone marrow chimeras in Ldlr-/- mice, NLRP3 inhibitor treatment, and IL-1β/plaque quantification","pmids":["28104796"],"confidence":"High","gaps":["Direct TET2 target genes upstream of NLRP3 not defined in this study","Did not establish whether effect is catalytic or scaffolding"]},{"year":2018,"claim":"Extended TET2 activity to RNA, showing mRNA m5C oxidation controls Socs3 transcript fate and JAK-STAT-driven myelopoiesis in an enzyme-dependent manner.","evidence":"Tet2 knockout infection models, RNA m5C-seq, mRNA stability assays, and ADAR1 knockdown epistasis","pmids":["29364877"],"confidence":"High","gaps":["Full set of physiological mRNA substrates not enumerated","How TET2 is targeted to specific transcripts unknown"]},{"year":2018,"claim":"Identified TET2 as a tumor-context restraint on engineered T cells, where its disruption enhances CAR T memory phenotype and potency.","evidence":"Clinical lentiviral integration mapping, ATAC-seq, and experimental TET2 knockdown in CAR T cells","pmids":["29849141"],"confidence":"High","gaps":["Molecular targets governing the central-memory program not pinpointed here","Catalytic dependence not directly tested"]},{"year":2019,"claim":"Defined cytokine-driven activation of TET2, showing JAK2 phosphorylates Y1939/Y1964 to boost enzymatic activity and couple TET2 to erythroid factor KLF1.","evidence":"Phospho-specific antibodies, in vitro kinase assays, Co-IP, JAK2V617F samples/models, and genome-wide methylation analysis","pmids":["30944118"],"confidence":"High","gaps":["Structural consequence of tyrosine phosphorylation on the catalytic domain unresolved","Phosphatase counter-regulation not addressed"]},{"year":2019,"claim":"Showed AMPK-dependent stabilization of TET2 via S97 phosphorylation and 14-3-3β binding links energy/metabolic signaling to 5-hmC and differentiation.","evidence":"In vitro kinase assay, Co-IP, CRISPR knockout, genome-wide 5-hmC mapping, and phosphomimetic rescue in C2C12 cells","pmids":["31164154"],"confidence":"High","gaps":["Stoichiometry and turnover kinetics of 14-3-3β stabilization not quantified","Generality beyond myogenic context untested"]},{"year":2019,"claim":"Established transcription-factor-directed recruitment, showing IFNγ-activated STAT1 brings TET2 to chemokine and PD-L1 loci to shape tumor immune infiltration.","evidence":"STAT1-TET2 Co-IP, ChIP, hMeDIP, conditional Tet2 KO tumor cells, and in vivo tumor models","pmids":["31310587"],"confidence":"High","gaps":["Whether STAT1 recruitment is catalytic-dependent at all loci not fully resolved","Direct versus indirect demethylation of PD-L1 locus not parsed"]},{"year":2020,"claim":"Demonstrated that TET2 modifies tRNA, depositing hm5C and influencing tRNA-fragment pools, broadening its RNA substrate repertoire.","evidence":"Endogenously tagged Tet2 CLIP-seq, mass spectrometry, and Tet2 knockout mESCs with hm5C immunoprecipitation","pmids":["33230319"],"confidence":"High","gaps":["Functional consequence of tRNA hm5C for translation not established","Specific tRNA species targeted not comprehensively mapped"]},{"year":2020,"claim":"Showed TET2 (with TET3) enforces peripheral B cell tolerance by promoting HDAC-dependent CD86 downregulation after chronic antigen exposure.","evidence":"B cell-specific Tet2/3 conditional KO, ChIP for HDAC1/2 at Cd86, chimeras, and anti-CD86 blockade","pmids":["32572241"],"confidence":"High","gaps":["Relative TET2 versus TET3 contribution not dissected","Catalytic dependence of CD86 control not isolated"]},{"year":2021,"claim":"Identified PROSER1 as a bridge enabling OGT-mediated TET2 GlcNAcylation and stability, controlling TET2 enhancer/CpG-island occupancy.","evidence":"Co-IP, genome-wide ChIP-seq, DNA methylation analysis, and PROSER1 knockout cells","pmids":["34667079"],"confidence":"High","gaps":["GlcNAcylation sites on TET2 not mapped","Causal chain from GlcNAcylation to chromatin recruitment incompletely resolved"]},{"year":2022,"claim":"Linked TET2 loss to inflammasome priming through a defined DNA-methylation circuit, showing DUSP10 silencing elevates JNK1-BRCC3-dependent NLRP3 activation.","evidence":"Isogenic murine/human macrophages, Dusp10 promoter methylation editing, BRCC3 inhibitor, and Abro1 epistasis","pmids":["37781816"],"confidence":"High","gaps":["Whether TET2 directly demethylates the Dusp10 promoter versus indirect effect not fully shown","Applicability across other inflammatory loci untested"]},{"year":2023,"claim":"Defined the genetic and transcriptional requirements for TET2-loss-driven CAR T expansion, identifying BATF3-MYC as the proliferative program TET2 restrains.","evidence":"Biallelic versus monoallelic TET2 disruption, BATF3 overexpression epistasis, transcriptomics, and in vivo models","pmids":["36755094"],"confidence":"High","gaps":["Direct TET2 targets at the BATF3/MYC axis not pinpointed","Mechanism of genomic instability under TET2 loss unresolved"]},{"year":2023,"claim":"Connected TET2's RNA m5C-eraser activity to leukemia stem cell homing, showing m5C accumulation on TSPAN13 mRNA is read by YBX1 to activate CXCR4/CXCL12 signaling.","evidence":"m5C RNA-seq, YBX1 RIP, CXCR4/CXCL12 assays, multiple AML mouse models, and human LSC transplantation","pmids":["37541212"],"confidence":"High","gaps":["Generality of YBX1-mediated stabilization across the m5C transcriptome not defined","Druggability of this axis in patients untested"]},{"year":2023,"claim":"Linked clonal expansion of TET2-haploinsufficient HSPCs to inflammatory signaling, showing IL-1R1-dependent IL-1 drives Tet2+/- self-renewal during aging.","evidence":"Bone marrow transplantation, Tet2+/flox mosaicism, IL-1 administration, IL-1R1 deletion epistasis, and pharmacologic IL-1 inhibition","pmids":["36379023"],"confidence":"High","gaps":["Direct molecular targets downstream of IL-1R1 in Tet2+/- HSCs not defined","Whether catalytic TET2 deficiency mediates IL-1 responsiveness unclear"]},{"year":2024,"claim":"Revealed TET2 controls chromatin compaction via RNA m5C oxidation, antagonizing MBD6-guided H2AK119ub deubiquitination and exposing a therapeutic vulnerability in TET2-mutant leukemia.","evidence":"RNA m5C mapping, H2AK119ub ChIP-seq, MBD6 Co-IP, CRISPR knockout of MBD6 in TET2-mutant cells, and TET2-loss mouse models","pmids":["39358506"],"confidence":"High","gaps":["How MBD6 m5C-reading is mechanistically coupled to the deubiquitinase machinery not fully resolved","Selectivity of MBD6 dependence across TET2-mutant subtypes not delineated"]},{"year":2024,"claim":"Defined proteostatic regulation of TET2, showing CUL7-FBXW11 drives its degradation while MEK1 phosphorylation at S1107 stabilizes it, governing TKI resistance via NF-κB.","evidence":"Co-IP, ubiquitination assays, phospho-site mutagenesis, and NF-κB inhibition in vitro and in vivo","pmids":["38461173"],"confidence":"Medium","gaps":["Single-lab finding without independent confirmation of the CUL7-FBXW11-TET2 axis","Direct TET2 targets repressing TNF/NF-κB not identified"]},{"year":null,"claim":"How TET2 substrate choice (DNA versus diverse RNA species), locus/transcript targeting by partner proteins, and the balance between catalytic and scaffolding functions are coordinated in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model distinguishing when TET2 acts on DNA versus RNA at a given locus","Targeting rules linking specific transcription-factor partners to genomic occupancy incomplete","Catalytic versus non-catalytic contributions not systematically separated across tissues"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,5,9,16]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0,1,22]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[4,9,10,11,28]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4,9,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,6,24,25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,15,25]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[10,23,25]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,10,25]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,22,24]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,9,11,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,6,8,30]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,7,26,29]}],"complexes":["TET2-OGT complex","TET2-Sin3a complex","VDR-STAT3-TET2 complex"],"partners":["OGT","STAT1","HDAC2","SIN3A","PML","FOXP1","MBD6","PROSER1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6N021","full_name":"Methylcytosine dioxygenase TET2","aliases":[],"length_aa":2002,"mass_kda":223.8,"function":"Dioxygenase that catalyzes the conversion of the modified genomic base 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) and plays a key role in active DNA demethylation. Has a preference for 5-hydroxymethylcytosine in CpG motifs. 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. Methylation at the C5 position of cytosine bases is an epigenetic modification of the mammalian genome which plays an important role in transcriptional regulation. 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","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q6N021/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TET2","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":"PSPC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TET2","total_profiled":1310},"omim":[{"mim_id":"620773","title":"PROLINE- AND SERINE-RICH PROTEIN 1; PROSER1","url":"https://www.omim.org/entry/620773"},{"mim_id":"619458","title":"METHYL-CpG-BINDING DOMAIN PROTEIN 6; MBD6","url":"https://www.omim.org/entry/619458"},{"mim_id":"619126","title":"IMMUNODEFICIENCY 75 WITH LYMPHOPROLIFERATION; IMD75","url":"https://www.omim.org/entry/619126"},{"mim_id":"616604","title":"CHROMOSOME 14q32 DUPLICATION SYNDROME, 700-KB","url":"https://www.omim.org/entry/616604"},{"mim_id":"614286","title":"MYELODYSPLASTIC SYNDROME; MDS","url":"https://www.omim.org/entry/614286"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TET2"},"hgnc":{"alias_symbol":["FLJ20032"],"prev_symbol":["KIAA1546"]},"alphafold":{"accession":"Q6N021","domains":[{"cath_id":"3.60.130","chopping":"1184-1202_1232-1420_1432-1464_1846-1935","consensus_level":"high","plddt":95.0124,"start":1184,"end":1935}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6N021","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6N021-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6N021-F1-predicted_aligned_error_v6.png","plddt_mean":47.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TET2","jax_strain_url":"https://www.jax.org/strain/search?query=TET2"},"sequence":{"accession":"Q6N021","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6N021.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6N021/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6N021"}},"corpus_meta":[{"pmid":"21130701","id":"PMC_21130701","title":"Leukemic 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with the methyl group oriented toward catalytic Fe(II); the catalytic cavity accommodates 5mC derivatives for further iterative oxidation.\",\n      \"method\": \"X-ray crystallography (2.02 Å), active-site mutagenesis of Fe(II)/NOG-chelating, DNA-interacting, and zinc-chelating residues\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional mutagenesis validation in a single rigorous study\",\n      \"pmids\": [\"24315485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IDH1/2 neomorphic mutations produce 2-hydroxyglutarate (2HG), which inhibits TET2 catalytic function in cells; expression of 2HG-producing IDH alleles impairs TET2-mediated DNA hydroxymethylation and induces global DNA hypermethylation phenotypically similar to TET2 loss-of-function; IDH1/2 mutations and TET2 mutations are mutually exclusive in AML and produce overlapping epigenetic defects.\",\n      \"method\": \"Mutational and epigenetic profiling of AML patient cohort; cellular expression of mutant IDH alleles with measurement of TET2 catalytic activity; genetic epistasis (mutual exclusivity analysis)\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (patient cohort genetics, cellular enzymatic assay, epigenetic profiling), replicated conceptually across multiple labs\",\n      \"pmids\": [\"21130701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TET2 and TET3 directly interact with O-GlcNAc transferase (OGT); TET2/3 promote OGT enzymatic activity without OGT influencing TET2/3 hydroxymethylation activity; TET2/3-OGT co-localize at active promoters enriched for H3K4me3; reduction of TET2/3 or OGT decreases H3K4me3 and transcription; HCF1 (a SET1/COMPASS component) is a specific GlcNAcylation target of TET2/3-OGT and its modification is important for SET1/COMPASS integrity; Tet2 knockout mouse bone marrow shows decreased global GlcNAcylation and H3K4me3.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, enzymatic activity assays, Tet2 knockout mouse bone marrow analysis, mass spectrometry\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods, validated in knockout mouse model\",\n      \"pmids\": [\"23353889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TET2 selectively represses IL-6 transcription during inflammation resolution in innate myeloid cells independently of its DNA methylation/hydroxymethylation enzymatic activity; IκBζ mediates specific targeting of TET2 to the Il6 promoter; TET2 recruits HDAC2 to repress IL-6 transcription via histone deacetylation.\",\n      \"method\": \"Tet2-deficient mouse model (endotoxin shock and colitis), ChIP, reporter assays, Co-immunoprecipitation of TET2 with HDAC2, catalytically inactive TET2 rescue experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, KO mouse phenotype, catalytic mutant rescue), single lab but rigorous\",\n      \"pmids\": [\"26287468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TET2 promotes infection-induced myelopoiesis through mRNA oxidation in an enzymatic-activity-dependent manner; TET2 mediates oxidation of 5-methylcytosine (m5C) in mRNA; TET2 deficiency leads to transcriptome-wide accumulation of m5C including in the 3'UTR of Socs3 mRNA, which influences double-stranded RNA formation for ADAR1 binding; TET2 represses Socs3 expression through ADAR1 (RNA editing-independent), reducing Socs3 mRNA stability and thereby relieving JAK-STAT pathway suppression to promote myelopoiesis.\",\n      \"method\": \"Tet2 knockout mouse models (sepsis and parasite infection), RNA m5C sequencing, mRNA stability assays, ADAR1 knockdown epistasis experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, m5C mapping, genetic epistasis in vivo), rigorous mechanistic dissection\",\n      \"pmids\": [\"29364877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JAK2 phosphorylates TET2 at tyrosines Y1939 and Y1964 in response to hematopoietic cytokines, activating TET2 enzymatic activity; phosphorylated TET2 interacts with the erythroid transcription factor KLF1, with this interaction enhanced by erythropoietin; activating JAK2V617F mutation increases TET2 activity, cytosine hydroxymethylation, and genome-wide loss of cytosine methylation.\",\n      \"method\": \"Phospho-specific antibodies, Co-immunoprecipitation, in vitro kinase assays, JAK2V617F patient samples and mouse models, genome-wide methylation analysis\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro kinase assay, Co-IP, patient samples and mouse models, multiple orthogonal methods\",\n      \"pmids\": [\"30944118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IFNγ stimulates STAT1 to bind TET2 and recruit TET2 to hydroxymethylate chemokine and PD-L1 gene loci; TET2 mediates IFNγ-JAK-STAT signaling to control chemokine expression, PD-L1 expression, and lymphocyte infiltration; deletion of Tet2 in murine tumor cells reduced chemokine expression and tumor-infiltrating lymphocytes.\",\n      \"method\": \"Co-immunoprecipitation (STAT1-TET2), ChIP, Tet2 conditional knockout in tumor cells, hMeDIP, in vivo tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP, conditional KO with defined phenotypic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"31310587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AMPK phosphorylates TET2 at serine S97, enhancing TET2 stability by promoting its binding to 14-3-3β; AMPK ablation results in decreased global 5-hmC levels and severe myogenic differentiation defects; phospho-mimicking TET2-S97E partially rescues differentiation defects in AMPK-null cells.\",\n      \"method\": \"In vitro kinase assay, Co-immunoprecipitation, CRISPR/Cas9 knockout, genome-wide 5-hmC mapping, AMPK-null C2C12 cells, phosphomimetic rescue\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay, Co-IP, CRISPR KO with functional rescue by phosphomimetic mutant\",\n      \"pmids\": [\"31164154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TET2-deficient macrophages exhibit increased NLRP3 inflammasome-mediated IL-1β secretion; partial bone marrow reconstitution with TET2-deficient cells is sufficient for clonal expansion and marked increase in atherosclerotic plaque size in Ldlr-/- mice; NLRP3 inhibition shows greater atheroprotective activity in TET2-deficient chimeric mice.\",\n      \"method\": \"Bone marrow transplantation (chimeric mice), NLRP3 inhibitor treatment, IL-1β measurement, plaque size quantification\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined cellular phenotype with genetic KO and pharmacological inhibitor, replicated across multiple experimental approaches\",\n      \"pmids\": [\"28104796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TET2 chemically modifies tRNAs by depositing the 5-hydroxymethylcytosine (hm5C) modification; TET2 is necessary and sufficient for hm5C deposition on tRNA as shown by mass spectrometry; Tet2 knockout in mESCs affects levels of small noncoding RNAs (tRNA fragments) enriched by hm5C immunoprecipitation.\",\n      \"method\": \"Stringent affinity-tag purification and crosslinking RNA immunoprecipitation-sequencing from endogenously-tagged Tet2, mass spectrometry, Tet2 knockout mESCs, hm5C immunoprecipitation\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mass spectrometry demonstrating necessity and sufficiency, endogenous tagging, multiple orthogonal methods in single study\",\n      \"pmids\": [\"33230319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TET2 oxidizes m5C on chromatin-associated retrotransposon RNA; MBD6 protein recognizes retrotransposon RNA m5C and guides deubiquitination of H2AK119ub to promote open chromatin; TET2 oxidizes m5C and antagonizes MBD6-dependent H2AK119ub deubiquitination; TET2 depletion leads to globally decreased H2AK119ub, more open chromatin, and increased transcription; MBD6 depletion selectively blocks proliferation of TET2-mutant leukemic cells.\",\n      \"method\": \"RNA m5C mapping, H2AK119ub ChIP-seq, MBD6 Co-IP, CRISPR knockout of MBD6 in TET2-mutant leukemic cells, mouse models of TET2-loss hematopoiesis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (RNA m5C mapping, ChIP-seq, Co-IP, genetic rescue), mechanistic dissection with therapeutic validation\",\n      \"pmids\": [\"39358506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TET2 deficiency in AML increases expression of TSPAN13 through accumulation of m5C modification on TSPAN13 mRNA; YBX1 specifically recognizes m5C-modified TSPAN13 mRNA and increases its stability and expression; increased TSPAN13 activates CXCR4/CXCL12 signaling, leading to increased homing/migration of leukemia stem cells into bone marrow niche, enhancing self-renewal.\",\n      \"method\": \"m5C RNA sequencing, RIP assays (YBX1), Co-IP, CXCR4/CXCL12 signaling assays, multiple AML mouse models, human LSC transplantation\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA m5C sequencing, Co-IP, multiple AML models with mechanistic pathway dissection\",\n      \"pmids\": [\"37541212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PROSER1 mediates the interaction between OGT and TET2, promoting TET2 O-GlcNAcylation and protein stability; loss of PROSER1 results in lower enrichment of TET2 at enhancers and CpG islands, with concomitant increase in DNA methylation; PROSER1, UTX, TET1/2, and OGT co-localize on enhancers and CpG islands genome-wide.\",\n      \"method\": \"Co-immunoprecipitation, genome-wide ChIP-seq, DNA methylation analysis, PROSER1 knockout cells, O-GlcNAcylation assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, KO with defined molecular phenotype, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"34667079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TET2 disruption in CAR T cells (via lentiviral integration) produces an epigenetic profile consistent with altered T cell differentiation and a central memory phenotype at peak expansion; experimental knockdown of TET2 recapitulates the potency-enhancing effect on CAR T cell expansion and anti-tumor activity.\",\n      \"method\": \"Clinical case analysis, lentiviral integration site mapping, ATAC-seq/epigenetic profiling, experimental TET2 knockdown in CAR T cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clinical observation validated by experimental TET2 knockdown with defined epigenetic and functional phenotype\",\n      \"pmids\": [\"29849141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TET2 loss enables antigen-independent CAR T cell clonal expansion; these clonal proliferations require biallelic TET2 disruption and sustained expression of BATF3 to drive a MYC-dependent proliferative program; TET2 acts as a guardian against BATF3-induced CAR T cell proliferation and genomic instability.\",\n      \"method\": \"Genetic TET2 disruption (biallelic vs monoallelic) in CAR T cells, BATF3 overexpression epistasis, transcriptomic analysis, in vivo tumor models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (biallelic vs monoallelic), BATF3 epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"36755094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PML physically binds TET2 via the PML C-terminal domain and recruits TET2 to PML-positive nuclear bodies; this interaction promotes 5-hmC formation in response to chemotherapeutic agents (doxorubicin); the PML-RARA t(15;17) fusion disrupts PML-TET2 interaction; knockout of PML abolishes doxorubicin-promoted DNA modification.\",\n      \"method\": \"SILAC-MS interactome, Co-immunoprecipitation, PML knockout cells, 5-hmC dot-blot assay, domain-mapping experiments\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SILAC-MS, Co-IP with domain mapping, KO validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"29735542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TET2 regulates mast cell differentiation through its catalytic (hydroxymethylation) activity affecting gene expression and enhancer 5-hmC deposition, while TET2 control of mast cell proliferation is strictly dependent on TET2 protein expression and cannot be rescued by catalytically inactive TET2.\",\n      \"method\": \"Tet2 knockout mouse-derived mast cells, re-expression of wild-type vs catalytically inactive TET2, genome-wide 5-hmC mapping, gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant rescue separating enzymatic vs non-enzymatic functions, genome-wide 5-hmC mapping, clean KO phenotype\",\n      \"pmids\": [\"27160912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TET2 binds NANOG in embryonic stem cells; TET2 protein expression is restricted to the naïve pluripotent state; TET2-negative ESCs lose the ability to form undifferentiated ESC colonies.\",\n      \"method\": \"CRISPR/Cas9 endogenous epitope-tagging of Tet2, Co-immunoprecipitation (TET2-NANOG), FACS sorting of TET2-reporter ESCs with colony-forming assay\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and endogenous tagging, single lab, NANOG interaction not fully characterized mechanistically\",\n      \"pmids\": [\"31582397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TET2 interacts with PPARγ and is required for PPARγ binding to target loci upon activation with Rosiglitazone; TET2 is necessary for Rosiglitazone-dependent gene activation of PPARγ targets with concomitant DNA demethylation at promoter regions; TET2 gain-of-function promotes insulin sensitivity in adipocytes.\",\n      \"method\": \"Co-immunoprecipitation (TET2-PPARγ), ChIP-PCR, DNA methylation analysis, siRNA knockdown/overexpression, insulin-stimulated glucose uptake assay\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, ChIP, functional assays, single lab with multiple methods but no structural validation\",\n      \"pmids\": [\"30193945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TET2 deficiency in macrophages leads to increased JNK1 phosphorylation through increased promoter methylation and decreased expression of the JNK-inactivating phosphatase DUSP10; increased JNK1 signaling leads to NLRP3 deubiquitylation and activation by the deubiquitinase BRCC3; targeted editing of DUSP10 promoter methylation abolished cholesterol-induced inflammasome activation in Tet2-deficient macrophages.\",\n      \"method\": \"Tet2-deficient murine and human ESC-derived isogenic macrophages, Dusp10 promoter methylation editing (active Tet1-deadCas9), BRCC3 inhibitor (holomycin), Abro1 hematopoietic KO epistasis, NLRP3 ubiquitylation assay\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches including promoter editing, pharmacological inhibition, genetic epistasis, and human cell validation\",\n      \"pmids\": [\"37781816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-1 receptor 1 (IL-1R1)-dependent signaling drives expansion of Tet2+/- hematopoietic stem and progenitor cells during aging; IL-1α-treated Tet2+/- HSCs show increased DNA replication and self-renewal transcriptomic signatures; genetic deletion of IL-1R1 in Tet2+/- HSPCs or pharmacologic inhibition of IL-1 signaling impairs Tet2+/- clonal expansion.\",\n      \"method\": \"Bone marrow transplantation mouse models, genetic mosaicism model (Tet2+/flox), IL-1 administration, IL-1R1 genetic deletion epistasis, IL-1 pharmacological inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (IL-1R1 deletion), pharmacological validation, multiple mouse model approaches\",\n      \"pmids\": [\"36379023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ETV2 directly interacts with TET2 (and TET1); ETV2-TET1/TET2 complexes demethylate the Robo4 proximal promoter and induce endothelial cell-specific Robo4 expression during iPS cell differentiation into endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation (ETV2-TET2), adenoviral overexpression of ETV2-TET1/TET2 in non-endothelial cells, reporter assay, bisulfite sequencing of Robo4 promoter\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, functional demethylation assay with overexpression system, single lab\",\n      \"pmids\": [\"29618782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1 promoters in mammary cells; Tet2 deletion impairs mammary luminal lineage commitment and reduces ERα expression, conferring tamoxifen resistance in vivo.\",\n      \"method\": \"Mammary-specific Tet2 conditional KO mouse, Co-immunoprecipitation (TET2-FOXP1), ChIP, bisulfite sequencing of ESR1/GATA3/FOXA1 promoters, Tet2-PyMT mammary tumor model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, bisulfite sequencing, conditional KO with defined in vivo phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"32934200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TET2 regulates the spatial redistribution of H3K9me3-marked heterochromatin; TET2 deficiency in HSPCs retains perinuclear distribution of heterochromatin and leads to upregulation of endogenous retroviruses (ERVs) and interferon-stimulated genes (ISGs), contributing to functional decline of aged HSPCs.\",\n      \"method\": \"TET2-deficient HSPCs, genome-wide H3K9me3 ChIP-seq, 3D nuclear imaging, reverse transcriptase inhibitor treatment, single-cell RNA-seq\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP-seq, 3D imaging, pharmacological rescue, single lab without full mechanistic reconstitution\",\n      \"pmids\": [\"37884767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Elevated CEBPA levels (driven by CEBPA N-terminal mutations) recruit TET2 to the Gata2 distal hematopoietic enhancer, increasing Gata2 expression; concurrent TET2 loss in CEBPA double-mutant AML increases Gata2 promoter methylation to rebalance GATA2 levels, conferring competitive advantage.\",\n      \"method\": \"CEBPA-TET2 co-mutated patient transcriptomic/epigenomic analysis, ChIP-seq, DNA methylation analysis, mouse models of CEBPA-TET2 co-mutation, demethylating agent treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq showing TET2 recruitment, epigenomic analysis, patient data and mouse models, multiple orthogonal methods\",\n      \"pmids\": [\"37794021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TET2 is enriched at active enhancers and promoters in embryonic stem cells where it demethylates DNA; TET2 partners with the histone deacetylase component Sin3a, co-localizing at promoters and active enhancers; TET2 deficiency diminishes Sin3a at these regions; combined loss of Tet1/2 (but not their catalytic activities) reduces Sin3a at active enhancers.\",\n      \"method\": \"Tet2 catalytic mutant and knockout ESCs, ChIP-seq, Co-immunoprecipitation (TET2-Sin3a), mass spectrometry, Tet1/2 double KO ESCs\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, catalytic mutant dissection, multiple ESC genetic models\",\n      \"pmids\": [\"37456851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TET2 is poly-ubiquitinated by E3 ligase CUL7-FBXW11 and degraded via proteasome in EGFR-TKI resistant NSCLC cells; MEK1 phosphorylates TET2 at Ser1107, stabilizing it, while MEK1 inactivation enhances CUL7-FBXW11 recruitment and TET2 proteasomal degradation; TET2 loss upregulates TNF/NF-κB signaling conferring EGFR-TKI resistance.\",\n      \"method\": \"Co-immunoprecipitation (TET2-CUL7-FBXW11, TET2-MEK1), ubiquitination assay, phospho-site mutagenesis, NF-κB inhibition in vitro and in vivo\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, phospho-mutagenesis, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"38461173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TET2 promotes CXCL5 expression through STAT3 binding to the CXCL5 promoter, driving neutrophil infiltration; TET2-mediated DNA demethylation is elevated during lung adeno-to-squamous transition (AST) and Tet2 is required for squamous transition.\",\n      \"method\": \"Tet2 conditional KO in KrasG12D/Lkb1 mouse model, STAT3 ChIP, CXCL5 promoter methylation analysis, neutrophil depletion experiments\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — ChIP, genetic KO in vivo model, single lab\",\n      \"pmids\": [\"38805014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TET2 functions as an mRNA m5C demethylase (eraser); TET2 deficiency leads to accumulation of m5C in mRNAs of urea cycle enzymes; YBX1-HuR binding is abolished by TET2-mediated m5C oxidation, promoting decay of urea cycle enzyme mRNAs; loss of TET2 increases arginine production through the urea cycle, activating mTORC1 signaling and promoting cell growth.\",\n      \"method\": \"mRNA m5C sequencing (MeRIP-seq), RIP assays (YBX1-HuR), urea cycle metabolite measurement, mTORC1 activity assays, TET2 KO tumor cell lines\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq, RIP assays, metabolic measurements, multiple cell line models, single lab\",\n      \"pmids\": [\"37550284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Vitamin D receptor (VDR) and JAK2-phosphorylated STAT3 interact with TET2 to form a complex; JAK2-mediated STAT3 phosphorylation is specific to vitamin D stimulation; VDR-STAT3-TET2 complex drives DNA demethylation and transcriptional activation at VDR binding sites during tolerogenic DC differentiation; pharmacological inhibition of JAK2 reverts vitamin D-induced tolerogenic properties.\",\n      \"method\": \"Co-immunoprecipitation (VDR-STAT3-TET2), JAK2 inhibitor treatment, genome-wide DNA methylation analysis, phospho-STAT3 analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP of triple complex, pharmacological validation, single lab\",\n      \"pmids\": [\"35045292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tet2 and Tet3 in B cells are required for downregulation of CD86 following chronic self-antigen exposure; Tet2/3-deficient B cells show decreased accumulation of HDAC1 and HDAC2 at the Cd86 locus; anti-CD86 blockade partially restricts aberrant T and B cell activation caused by Tet2/3 deficiency.\",\n      \"method\": \"Tet2/3 conditional B cell-specific KO mice, ChIP (HDAC1/2 at Cd86), mixed bone marrow chimeras, anti-CD86 antibody blockade\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined molecular mechanism (ChIP), functional rescue with antibody blockade, multiple experimental approaches\",\n      \"pmids\": [\"32572241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Leptin suppresses adipocyte TET2 levels via JAK2-STAT3 signaling; TET2 interacts with C/EBPα and increases 5-hydroxymethylcytosine levels at the leptin gene promoter, thereby promoting leptin gene expression; adipocyte TET2 deficiency reduces leptin levels and improves leptin sensitivity in obese mice.\",\n      \"method\": \"Co-immunoprecipitation (TET2-C/EBPα), JAK2-STAT3 inhibition, hMeDIP at leptin promoter, adipocyte-specific Tet2 KO mice, leptin measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, hMeDIP, conditional KO with defined phenotype, signaling pathway dissection, single lab\",\n      \"pmids\": [\"38561362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TET2 binds endogenous androgen receptor (AR) and AR-coactivator proteins in prostate cancer cells; TET2 knockdown increases PSA (KLK3) expression; TET2 binding sites and 5-hydroxymethylcytosine are found proximal to KLK3; TET2 knockdown increases LNCaP cell proliferation and migration.\",\n      \"method\": \"Co-immunoprecipitation (TET2-AR), siRNA knockdown, published ChIP-seq and 5-hmC mapping, cell proliferation and migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, siRNA KD with functional readouts, relied partly on published ChIP data, single lab\",\n      \"pmids\": [\"27819678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tet2 deficiency in myeloid cells promotes renal macrophage infiltration, NLRP3 inflammasome activation, elevated IL-1β and IL-18, and sodium retention activating NCC and NKCC2 transporters, sensitizing mice to hypertension; NLRP3 inhibitor MCC950 reversed hypertensive state and sodium retention in Tet2-deficient chimeric mice.\",\n      \"method\": \"Bone marrow transplantation (Tet2-/- chimeras), Angiotensin II subpressor dose challenge, NLRP3 inhibitor treatment, renal transporter phosphorylation analysis, cytokine measurement\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with pharmacological rescue, defined molecular pathway (NLRP3-IL-1β-sodium transporter), multiple readouts\",\n      \"pmids\": [\"39234670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tet2 modulates M2 macrophage polarization by demethylating m5C in mRNAs of M2-related genes Klf4 and Rock1; Tet2 deficiency decreases mRNA m5C demethylation of Klf4 and Rock1, contributing to M2 polarization; Tet2-/- mice show increased AR severity and macrophage M2 skewing.\",\n      \"method\": \"MeRIP-qPCR (m5C on Klf4 and Rock1 mRNA), Tet2 KO mice (OVA-AR model), BMDMs from WT and Tet2-/- mice, RNA sequencing\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — MeRIP-qPCR, KO mouse model with in vitro validation, single lab\",\n      \"pmids\": [\"39486186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TET2-mediated 5-hmC modification at the ZO-1 (tight junction) promoter region regulates ZO-1 expression in cerebral vascular endothelial cells; ROS (H2O2) decreases TET2-mediated 5-hmC at the ZO-1 promoter and reduces ZO-1 expression; Tet2 KO mice show reduced 5-hmC in endothelial cells and reduced ZO-1 expression.\",\n      \"method\": \"Tet2 KO mice, siRNA knockdown, hMeChIP-PCR at ZO-1 promoter, H2O2 treatment, BBB permeability assays\",\n      \"journal\": \"Fluids and barriers of the CNS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — hMeChIP-PCR, KO mouse and siRNA knockdown, functional BBB assay, single lab\",\n      \"pmids\": [\"36076297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TET2 regulates osteoclast differentiation by inhibiting BCL2 expression, which allows BECN1-dependent autophagy; TET2 knockdown increases BCL2 expression and BCL2-BECN1 binding, thereby suppressing autophagy and impairing osteoclast differentiation; siRNA knockdown of Bcl2 in Tet2-knockdown cells partially rescues autophagy and osteoclast differentiation.\",\n      \"method\": \"Tet2 siRNA knockdown, Co-IP (BCL2-BECN1), Bcl2 siRNA epistasis, autophagy assays, OVX mouse model with LV-shTet2\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP, epistasis via double knockdown, in vivo lentiviral KD, single lab\",\n      \"pmids\": [\"35255774\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TET2 is an Fe(II)- and α-ketoglutarate-dependent dioxygenase that iteratively oxidizes 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives in DNA (and m5C in RNA including mRNAs, tRNAs, and retrotransposon RNAs), acting as a DNA/RNA demethylase whose activity is activated by JAK2-mediated phosphorylation (Y1939/Y1964) and AMPK-mediated phosphorylation (S97, enhancing stability via 14-3-3β binding), inhibited by 2-hydroxyglutarate (produced by mutant IDH1/2), and regulated by proteasomal degradation via CUL7-FBXW11 (counteracted by MEK1 phosphorylation); TET2 functions in multiprotein complexes—interacting with OGT to promote GlcNAcylation and H3K4me3 via SET1/COMPASS, with HDAC2 to repress IL-6 transcription independently of its catalytic activity, with STAT1 downstream of IFNγ-JAK signaling to hydroxymethylate chemokine and PD-L1 loci, with BATF3/MYC to restrain CAR T cell proliferation, and with Sin3a at active enhancers—while RNA m5C oxidation by TET2 antagonizes MBD6-dependent H2AK119ub deubiquitination to maintain chromatin compaction, collectively establishing TET2 as a multi-substrate epigenetic regulator that integrates extracellular signals with DNA/RNA methylation status to govern hematopoietic stem cell self-renewal, immune cell differentiation, and inflammatory responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TET2 is an Fe(II)- and α-ketoglutarate-dependent dioxygenase that integrates extracellular signaling with the methylation status of DNA and RNA to govern hematopoietic stem cell self-renewal, immune cell differentiation, and inflammatory responses [#1, #8]. Its catalytic domain, formed when two zinc fingers bring together the Cys-rich and double-stranded β-helix (DSBH) domains, recognizes CpG dinucleotides and inserts 5-methylcytosine into the catalytic cavity to position the methyl group toward catalytic Fe(II), enabling iterative oxidation of 5mC to 5-hydroxymethylcytosine and further derivatives [#0]; this activity is blocked by 2-hydroxyglutarate produced by neomorphic IDH1/2 mutations, which phenocopies TET2 loss and is mutually exclusive with TET2 mutation in AML [#1]. Beyond DNA, TET2 oxidizes 5-methylcytosine in mRNAs, tRNAs, and chromatin-associated retrotransposon RNA, functioning as an RNA m5C eraser that controls transcript stability and chromatin state—destabilizing Socs3, TSPAN13, and urea-cycle enzyme mRNAs through m5C readers such as ADAR1, YBX1, and HuR, and antagonizing MBD6-guided H2AK119ub deubiquitination to maintain chromatin compaction [#4, #10, #11, #28]. TET2 catalytic output is tuned by post-translational signals: JAK2 phosphorylates Y1939/Y1964 to activate the enzyme downstream of hematopoietic cytokines, AMPK phosphorylates S97 to stabilize TET2 via 14-3-3β binding, and CUL7-FBXW11-mediated ubiquitination drives proteasomal degradation that MEK1 phosphorylation opposes [#5, #7, #26]. TET2 also acts within multiprotein complexes—stimulating OGT-dependent GlcNAcylation and H3K4me3 via SET1/COMPASS, partnering with Sin3a at active enhancers, and being recruited to specific loci by transcription factors and STAT proteins (STAT1, STAT3) downstream of IFNγ and other cytokines to demethylate or hydroxymethylate target genes [#2, #25, #6, #29]. A distinct, catalytically independent function recruits HDAC2 to the Il6 promoter via IκBζ to repress IL-6 during inflammation resolution, and TET2 loss broadly de-represses inflammatory programs including NLRP3 inflammasome activation [#3, #8]. Through these activities TET2 restrains clonal expansion of hematopoietic cells, and its loss confers selective advantages in clonal hematopoiesis, atherosclerosis, and CAR T cell proliferation [#8, #14, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that TET2 catalytic function can be antagonized in trans, linking a metabolic oncometabolite to TET2-type epigenetic defects and uniting two AML mutation classes mechanistically.\",\n      \"evidence\": \"AML cohort genetics, cellular expression of mutant IDH alleles with catalytic activity measurement, and mutual-exclusivity epistasis\",\n      \"pmids\": [\"21130701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which TET2 genomic targets drive the leukemic phenotype\", \"2HG inhibition mechanism inferred in cells, not from purified enzyme kinetics here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined the structural basis for how TET2 recognizes 5mC within CpG context and positions it for iterative oxidation, anchoring all downstream catalytic interpretations.\",\n      \"evidence\": \"2.02 Å X-ray crystal structure of TET2 bound to methylated DNA with active-site mutagenesis\",\n      \"pmids\": [\"24315485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure captured DNA substrate only; no structural insight into RNA substrate engagement\", \"Does not address regulation by post-translational modification or partners\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that TET2 acts non-catalytically as a scaffold coupling OGT-mediated GlcNAcylation to active chromatin, expanding its role beyond demethylation.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, enzymatic assays, mass spectrometry of HCF1, and Tet2 knockout mouse bone marrow\",\n      \"pmids\": [\"23353889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TET2 enhances OGT activity at the molecular level unresolved\", \"Relative contribution of OGT scaffolding versus DNA demethylation to H3K4me3 not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated a catalysis-independent repressive function, showing TET2 recruits HDAC2 to silence Il6 during inflammation resolution.\",\n      \"evidence\": \"Tet2-deficient mouse inflammation models, ChIP, Co-IP, and catalytically inactive TET2 rescue\",\n      \"pmids\": [\"26287468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of IκBζ-mediated targeting to other loci unknown\", \"Structural basis of TET2-HDAC2 interaction not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Separated TET2's catalytic and non-catalytic roles in a single lineage, showing differentiation depends on hydroxymethylation while proliferation control needs only protein presence.\",\n      \"evidence\": \"Tet2 knockout mast cells with wild-type versus catalytically inactive re-expression and genome-wide 5-hmC mapping\",\n      \"pmids\": [\"27160912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Non-catalytic proliferation-control partners not identified\", \"Mechanism distinguishing the two functions at specific loci unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected TET2 loss to a discrete inflammatory mechanism driving disease, showing TET2-deficient macrophages hyperactivate the NLRP3 inflammasome to accelerate atherosclerosis.\",\n      \"evidence\": \"Bone marrow chimeras in Ldlr-/- mice, NLRP3 inhibitor treatment, and IL-1β/plaque quantification\",\n      \"pmids\": [\"28104796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TET2 target genes upstream of NLRP3 not defined in this study\", \"Did not establish whether effect is catalytic or scaffolding\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended TET2 activity to RNA, showing mRNA m5C oxidation controls Socs3 transcript fate and JAK-STAT-driven myelopoiesis in an enzyme-dependent manner.\",\n      \"evidence\": \"Tet2 knockout infection models, RNA m5C-seq, mRNA stability assays, and ADAR1 knockdown epistasis\",\n      \"pmids\": [\"29364877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of physiological mRNA substrates not enumerated\", \"How TET2 is targeted to specific transcripts unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified TET2 as a tumor-context restraint on engineered T cells, where its disruption enhances CAR T memory phenotype and potency.\",\n      \"evidence\": \"Clinical lentiviral integration mapping, ATAC-seq, and experimental TET2 knockdown in CAR T cells\",\n      \"pmids\": [\"29849141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets governing the central-memory program not pinpointed here\", \"Catalytic dependence not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined cytokine-driven activation of TET2, showing JAK2 phosphorylates Y1939/Y1964 to boost enzymatic activity and couple TET2 to erythroid factor KLF1.\",\n      \"evidence\": \"Phospho-specific antibodies, in vitro kinase assays, Co-IP, JAK2V617F samples/models, and genome-wide methylation analysis\",\n      \"pmids\": [\"30944118\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural consequence of tyrosine phosphorylation on the catalytic domain unresolved\", \"Phosphatase counter-regulation not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed AMPK-dependent stabilization of TET2 via S97 phosphorylation and 14-3-3β binding links energy/metabolic signaling to 5-hmC and differentiation.\",\n      \"evidence\": \"In vitro kinase assay, Co-IP, CRISPR knockout, genome-wide 5-hmC mapping, and phosphomimetic rescue in C2C12 cells\",\n      \"pmids\": [\"31164154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and turnover kinetics of 14-3-3β stabilization not quantified\", \"Generality beyond myogenic context untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established transcription-factor-directed recruitment, showing IFNγ-activated STAT1 brings TET2 to chemokine and PD-L1 loci to shape tumor immune infiltration.\",\n      \"evidence\": \"STAT1-TET2 Co-IP, ChIP, hMeDIP, conditional Tet2 KO tumor cells, and in vivo tumor models\",\n      \"pmids\": [\"31310587\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT1 recruitment is catalytic-dependent at all loci not fully resolved\", \"Direct versus indirect demethylation of PD-L1 locus not parsed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that TET2 modifies tRNA, depositing hm5C and influencing tRNA-fragment pools, broadening its RNA substrate repertoire.\",\n      \"evidence\": \"Endogenously tagged Tet2 CLIP-seq, mass spectrometry, and Tet2 knockout mESCs with hm5C immunoprecipitation\",\n      \"pmids\": [\"33230319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of tRNA hm5C for translation not established\", \"Specific tRNA species targeted not comprehensively mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed TET2 (with TET3) enforces peripheral B cell tolerance by promoting HDAC-dependent CD86 downregulation after chronic antigen exposure.\",\n      \"evidence\": \"B cell-specific Tet2/3 conditional KO, ChIP for HDAC1/2 at Cd86, chimeras, and anti-CD86 blockade\",\n      \"pmids\": [\"32572241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative TET2 versus TET3 contribution not dissected\", \"Catalytic dependence of CD86 control not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified PROSER1 as a bridge enabling OGT-mediated TET2 GlcNAcylation and stability, controlling TET2 enhancer/CpG-island occupancy.\",\n      \"evidence\": \"Co-IP, genome-wide ChIP-seq, DNA methylation analysis, and PROSER1 knockout cells\",\n      \"pmids\": [\"34667079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"GlcNAcylation sites on TET2 not mapped\", \"Causal chain from GlcNAcylation to chromatin recruitment incompletely resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked TET2 loss to inflammasome priming through a defined DNA-methylation circuit, showing DUSP10 silencing elevates JNK1-BRCC3-dependent NLRP3 activation.\",\n      \"evidence\": \"Isogenic murine/human macrophages, Dusp10 promoter methylation editing, BRCC3 inhibitor, and Abro1 epistasis\",\n      \"pmids\": [\"37781816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TET2 directly demethylates the Dusp10 promoter versus indirect effect not fully shown\", \"Applicability across other inflammatory loci untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined the genetic and transcriptional requirements for TET2-loss-driven CAR T expansion, identifying BATF3-MYC as the proliferative program TET2 restrains.\",\n      \"evidence\": \"Biallelic versus monoallelic TET2 disruption, BATF3 overexpression epistasis, transcriptomics, and in vivo models\",\n      \"pmids\": [\"36755094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TET2 targets at the BATF3/MYC axis not pinpointed\", \"Mechanism of genomic instability under TET2 loss unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected TET2's RNA m5C-eraser activity to leukemia stem cell homing, showing m5C accumulation on TSPAN13 mRNA is read by YBX1 to activate CXCR4/CXCL12 signaling.\",\n      \"evidence\": \"m5C RNA-seq, YBX1 RIP, CXCR4/CXCL12 assays, multiple AML mouse models, and human LSC transplantation\",\n      \"pmids\": [\"37541212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of YBX1-mediated stabilization across the m5C transcriptome not defined\", \"Druggability of this axis in patients untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked clonal expansion of TET2-haploinsufficient HSPCs to inflammatory signaling, showing IL-1R1-dependent IL-1 drives Tet2+/- self-renewal during aging.\",\n      \"evidence\": \"Bone marrow transplantation, Tet2+/flox mosaicism, IL-1 administration, IL-1R1 deletion epistasis, and pharmacologic IL-1 inhibition\",\n      \"pmids\": [\"36379023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular targets downstream of IL-1R1 in Tet2+/- HSCs not defined\", \"Whether catalytic TET2 deficiency mediates IL-1 responsiveness unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed TET2 controls chromatin compaction via RNA m5C oxidation, antagonizing MBD6-guided H2AK119ub deubiquitination and exposing a therapeutic vulnerability in TET2-mutant leukemia.\",\n      \"evidence\": \"RNA m5C mapping, H2AK119ub ChIP-seq, MBD6 Co-IP, CRISPR knockout of MBD6 in TET2-mutant cells, and TET2-loss mouse models\",\n      \"pmids\": [\"39358506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MBD6 m5C-reading is mechanistically coupled to the deubiquitinase machinery not fully resolved\", \"Selectivity of MBD6 dependence across TET2-mutant subtypes not delineated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined proteostatic regulation of TET2, showing CUL7-FBXW11 drives its degradation while MEK1 phosphorylation at S1107 stabilizes it, governing TKI resistance via NF-κB.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, phospho-site mutagenesis, and NF-κB inhibition in vitro and in vivo\",\n      \"pmids\": [\"38461173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent confirmation of the CUL7-FBXW11-TET2 axis\", \"Direct TET2 targets repressing TNF/NF-κB not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TET2 substrate choice (DNA versus diverse RNA species), locus/transcript targeting by partner proteins, and the balance between catalytic and scaffolding functions are coordinated in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model distinguishing when TET2 acts on DNA versus RNA at a given locus\", \"Targeting rules linking specific transcription-factor partners to genomic occupancy incomplete\", \"Catalytic versus non-catalytic contributions not systematically separated across tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 5, 9, 16]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0, 1, 22]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [4, 9, 10, 11, 28]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 9, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 6, 24, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 15, 25]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [10, 23, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 10, 25]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 22, 24]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 9, 11, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 6, 8, 30]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 7, 26, 29]}\n    ],\n    \"complexes\": [\"TET2-OGT complex\", \"TET2-Sin3a complex\", \"VDR-STAT3-TET2 complex\"],\n    \"partners\": [\"OGT\", \"STAT1\", \"HDAC2\", \"Sin3a\", \"PML\", \"FOXP1\", \"MBD6\", \"PROSER1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}