Affinage

TET2

Methylcytosine dioxygenase TET2 · UniProt Q6N021

Length
2002 aa
Mass
223.8 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2010 High

    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

    PMID:21130701

    Open questions at the time
    • Did not resolve which TET2 genomic targets drive the leukemic phenotype
    • 2HG inhibition mechanism inferred in cells, not from purified enzyme kinetics here
  2. 2013 High

    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

    PMID:24315485

    Open questions at the time
    • Structure captured DNA substrate only; no structural insight into RNA substrate engagement
    • Does not address regulation by post-translational modification or partners
  3. 2013 High

    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

    PMID:23353889

    Open questions at the time
    • How TET2 enhances OGT activity at the molecular level unresolved
    • Relative contribution of OGT scaffolding versus DNA demethylation to H3K4me3 not separated
  4. 2015 High

    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

    PMID:26287468

    Open questions at the time
    • Generality of IκBζ-mediated targeting to other loci unknown
    • Structural basis of TET2-HDAC2 interaction not defined
  5. 2016 High

    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

    PMID:27160912

    Open questions at the time
    • Non-catalytic proliferation-control partners not identified
    • Mechanism distinguishing the two functions at specific loci unclear
  6. 2017 High

    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

    PMID:28104796

    Open questions at the time
    • Direct TET2 target genes upstream of NLRP3 not defined in this study
    • Did not establish whether effect is catalytic or scaffolding
  7. 2018 High

    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

    PMID:29364877

    Open questions at the time
    • Full set of physiological mRNA substrates not enumerated
    • How TET2 is targeted to specific transcripts unknown
  8. 2018 High

    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

    PMID:29849141

    Open questions at the time
    • Molecular targets governing the central-memory program not pinpointed here
    • Catalytic dependence not directly tested
  9. 2019 High

    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

    PMID:30944118

    Open questions at the time
    • Structural consequence of tyrosine phosphorylation on the catalytic domain unresolved
    • Phosphatase counter-regulation not addressed
  10. 2019 High

    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

    PMID:31164154

    Open questions at the time
    • Stoichiometry and turnover kinetics of 14-3-3β stabilization not quantified
    • Generality beyond myogenic context untested
  11. 2019 High

    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

    PMID:31310587

    Open questions at the time
    • Whether STAT1 recruitment is catalytic-dependent at all loci not fully resolved
    • Direct versus indirect demethylation of PD-L1 locus not parsed
  12. 2020 High

    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

    PMID:33230319

    Open questions at the time
    • Functional consequence of tRNA hm5C for translation not established
    • Specific tRNA species targeted not comprehensively mapped
  13. 2020 High

    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

    PMID:32572241

    Open questions at the time
    • Relative TET2 versus TET3 contribution not dissected
    • Catalytic dependence of CD86 control not isolated
  14. 2021 High

    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

    PMID:34667079

    Open questions at the time
    • GlcNAcylation sites on TET2 not mapped
    • Causal chain from GlcNAcylation to chromatin recruitment incompletely resolved
  15. 2022 High

    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

    PMID:37781816

    Open questions at the time
    • Whether TET2 directly demethylates the Dusp10 promoter versus indirect effect not fully shown
    • Applicability across other inflammatory loci untested
  16. 2023 High

    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

    PMID:36755094

    Open questions at the time
    • Direct TET2 targets at the BATF3/MYC axis not pinpointed
    • Mechanism of genomic instability under TET2 loss unresolved
  17. 2023 High

    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

    PMID:37541212

    Open questions at the time
    • Generality of YBX1-mediated stabilization across the m5C transcriptome not defined
    • Druggability of this axis in patients untested
  18. 2023 High

    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

    PMID:36379023

    Open questions at the time
    • Direct molecular targets downstream of IL-1R1 in Tet2+/- HSCs not defined
    • Whether catalytic TET2 deficiency mediates IL-1 responsiveness unclear
  19. 2024 High

    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

    PMID:39358506

    Open questions at the time
    • How MBD6 m5C-reading is mechanistically coupled to the deubiquitinase machinery not fully resolved
    • Selectivity of MBD6 dependence across TET2-mutant subtypes not delineated
  20. 2024 Medium

    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

    PMID:38461173

    Open questions at the time
    • Single-lab finding without independent confirmation of the CUL7-FBXW11-TET2 axis
    • Direct TET2 targets repressing TNF/NF-κB not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0140098 catalytic activity, acting on RNA 5 GO:0140110 transcription regulator activity 4 GO:0003723 RNA binding 3 GO:0140097 catalytic activity, acting on DNA 3 GO:0003677 DNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-8953854 Metabolism of RNA 4 R-HSA-4839726 Chromatin organization 3
Partners
FOXP1HDAC2MBD6OGTPMLPROSER1SIN3ASTAT1
Complex memberships
TET2-OGT complexTET2-Sin3a complexVDR-STAT3-TET2 complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 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. X-ray crystallography (2.02 Å), active-site mutagenesis of Fe(II)/NOG-chelating, DNA-interacting, and zinc-chelating residues Cell High 24315485
2010 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. 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) Cancer cell High 21130701
2013 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. Co-immunoprecipitation, ChIP, enzymatic activity assays, Tet2 knockout mouse bone marrow analysis, mass spectrometry The EMBO journal High 23353889
2015 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. Tet2-deficient mouse model (endotoxin shock and colitis), ChIP, reporter assays, Co-immunoprecipitation of TET2 with HDAC2, catalytically inactive TET2 rescue experiments Nature High 26287468
2018 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. Tet2 knockout mouse models (sepsis and parasite infection), RNA m5C sequencing, mRNA stability assays, ADAR1 knockdown epistasis experiments Nature High 29364877
2019 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. Phospho-specific antibodies, Co-immunoprecipitation, in vitro kinase assays, JAK2V617F patient samples and mouse models, genome-wide methylation analysis Cancer discovery High 30944118
2019 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. Co-immunoprecipitation (STAT1-TET2), ChIP, Tet2 conditional knockout in tumor cells, hMeDIP, in vivo tumor models The Journal of clinical investigation High 31310587
2019 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. In vitro kinase assay, Co-immunoprecipitation, CRISPR/Cas9 knockout, genome-wide 5-hmC mapping, AMPK-null C2C12 cells, phosphomimetic rescue Epigenetics & chromatin High 31164154
2017 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. Bone marrow transplantation (chimeric mice), NLRP3 inhibitor treatment, IL-1β measurement, plaque size quantification Science (New York, N.Y.) High 28104796
2020 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. Stringent affinity-tag purification and crosslinking RNA immunoprecipitation-sequencing from endogenously-tagged Tet2, mass spectrometry, Tet2 knockout mESCs, hm5C immunoprecipitation Nature structural & molecular biology High 33230319
2024 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. RNA m5C mapping, H2AK119ub ChIP-seq, MBD6 Co-IP, CRISPR knockout of MBD6 in TET2-mutant leukemic cells, mouse models of TET2-loss hematopoiesis Nature High 39358506
2023 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. m5C RNA sequencing, RIP assays (YBX1), Co-IP, CXCR4/CXCL12 signaling assays, multiple AML mouse models, human LSC transplantation Cell stem cell High 37541212
2021 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. Co-immunoprecipitation, genome-wide ChIP-seq, DNA methylation analysis, PROSER1 knockout cells, O-GlcNAcylation assays Life science alliance High 34667079
2018 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. Clinical case analysis, lentiviral integration site mapping, ATAC-seq/epigenetic profiling, experimental TET2 knockdown in CAR T cells Nature High 29849141
2023 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. Genetic TET2 disruption (biallelic vs monoallelic) in CAR T cells, BATF3 overexpression epistasis, transcriptomic analysis, in vivo tumor models Nature High 36755094
2018 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. SILAC-MS interactome, Co-immunoprecipitation, PML knockout cells, 5-hmC dot-blot assay, domain-mapping experiments Cancer research High 29735542
2016 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. Tet2 knockout mouse-derived mast cells, re-expression of wild-type vs catalytically inactive TET2, genome-wide 5-hmC mapping, gene expression analysis Cell reports High 27160912
2019 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. CRISPR/Cas9 endogenous epitope-tagging of Tet2, Co-immunoprecipitation (TET2-NANOG), FACS sorting of TET2-reporter ESCs with colony-forming assay Life science alliance Medium 31582397
2018 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. Co-immunoprecipitation (TET2-PPARγ), ChIP-PCR, DNA methylation analysis, siRNA knockdown/overexpression, insulin-stimulated glucose uptake assay Metabolism: clinical and experimental Medium 30193945
2022 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. 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 Circulation High 37781816
2023 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. Bone marrow transplantation mouse models, genetic mosaicism model (Tet2+/flox), IL-1 administration, IL-1R1 genetic deletion epistasis, IL-1 pharmacological inhibition Blood High 36379023
2018 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. Co-immunoprecipitation (ETV2-TET2), adenoviral overexpression of ETV2-TET1/TET2 in non-endothelial cells, reporter assay, bisulfite sequencing of Robo4 promoter Scientific reports Medium 29618782
2019 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. Mammary-specific Tet2 conditional KO mouse, Co-immunoprecipitation (TET2-FOXP1), ChIP, bisulfite sequencing of ESR1/GATA3/FOXA1 promoters, Tet2-PyMT mammary tumor model Nature communications High 32934200
2023 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. TET2-deficient HSPCs, genome-wide H3K9me3 ChIP-seq, 3D nuclear imaging, reverse transcriptase inhibitor treatment, single-cell RNA-seq Nature aging Medium 37884767
2023 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. CEBPA-TET2 co-mutated patient transcriptomic/epigenomic analysis, ChIP-seq, DNA methylation analysis, mouse models of CEBPA-TET2 co-mutation, demethylating agent treatment Nature communications Medium 37794021
2023 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. Tet2 catalytic mutant and knockout ESCs, ChIP-seq, Co-immunoprecipitation (TET2-Sin3a), mass spectrometry, Tet1/2 double KO ESCs iScience Medium 37456851
2024 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. Co-immunoprecipitation (TET2-CUL7-FBXW11, TET2-MEK1), ubiquitination assay, phospho-site mutagenesis, NF-κB inhibition in vitro and in vivo Signal transduction and targeted therapy Medium 38461173
2024 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. Tet2 conditional KO in KrasG12D/Lkb1 mouse model, STAT3 ChIP, CXCL5 promoter methylation analysis, neutrophil depletion experiments The Journal of experimental medicine Medium 38805014
2023 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. mRNA m5C sequencing (MeRIP-seq), RIP assays (YBX1-HuR), urea cycle metabolite measurement, mTORC1 activity assays, TET2 KO tumor cell lines Cell discovery Medium 37550284
2022 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. Co-immunoprecipitation (VDR-STAT3-TET2), JAK2 inhibitor treatment, genome-wide DNA methylation analysis, phospho-STAT3 analysis Cell reports Medium 35045292
2020 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. Tet2/3 conditional B cell-specific KO mice, ChIP (HDAC1/2 at Cd86), mixed bone marrow chimeras, anti-CD86 antibody blockade Nature immunology High 32572241
2024 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. Co-immunoprecipitation (TET2-C/EBPα), JAK2-STAT3 inhibition, hMeDIP at leptin promoter, adipocyte-specific Tet2 KO mice, leptin measurement Nature communications Medium 38561362
2016 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. Co-immunoprecipitation (TET2-AR), siRNA knockdown, published ChIP-seq and 5-hmC mapping, cell proliferation and migration assays Oncogene Medium 27819678
2024 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. Bone marrow transplantation (Tet2-/- chimeras), Angiotensin II subpressor dose challenge, NLRP3 inhibitor treatment, renal transporter phosphorylation analysis, cytokine measurement Circulation research Medium 39234670
2024 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. MeRIP-qPCR (m5C on Klf4 and Rock1 mRNA), Tet2 KO mice (OVA-AR model), BMDMs from WT and Tet2-/- mice, RNA sequencing International immunopharmacology Medium 39486186
2022 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. Tet2 KO mice, siRNA knockdown, hMeChIP-PCR at ZO-1 promoter, H2O2 treatment, BBB permeability assays Fluids and barriers of the CNS Medium 36076297
2018 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. Tet2 siRNA knockdown, Co-IP (BCL2-BECN1), Bcl2 siRNA epistasis, autophagy assays, OVX mouse model with LV-shTet2 Autophagy Medium 35255774

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer cell 2260 21130701
2017 Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science (New York, N.Y.) 1257 28104796
2018 Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 737 29849141
2015 Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 680 26287468
2017 Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell 602 28823558
2013 TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS. The EMBO journal 411 23353889
2013 Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation. Cell 344 24315485
2013 The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases. Leukemia 222 24220273
2018 Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation. Nature 219 29364877
2009 TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. Haematologica 199 19797729
2019 Tumor suppressor TET2 promotes cancer immunity and immunotherapy efficacy. The Journal of clinical investigation 190 31310587
2019 Loss of TET2 and TET3 in regulatory T cells unleashes effector function. Nature communications 138 31043609
2023 Aging drives Tet2+/- clonal hematopoiesis via IL-1 signaling. Blood 133 36379023
2023 TET2 guards against unchecked BATF3-induced CAR T cell expansion. Nature 129 36755094
2022 Mutant IDH Inhibits IFNγ-TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma. Cancer discovery 123 34848557
2018 OxLDL induces vascular endothelial cell pyroptosis through miR-125a-5p/TET2 pathway. Journal of cellular physiology 122 30370524
2020 Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension. Circulation 101 32192357
2020 The function and regulation of TET2 in innate immunity and inflammation. Protein & cell 99 33085059
2018 Tet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter. Nature communications 99 29858571
2014 TET2 as an epigenetic master regulator for normal and malignant hematopoiesis. Cancer science 97 25040794
2019 TET2 Function in Hematopoietic Malignancies, Immune Regulation, and DNA Repair. Frontiers in oncology 96 31001476
2018 TET2 controls chemoresistant slow-cycling cancer cell survival and tumor recurrence. The Journal of clinical investigation 94 29944140
2023 TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal. Cell stem cell 87 37541212
2019 TET2 Regulates the Neuroinflammatory Response in Microglia. Cell reports 85 31618637
2019 Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans. Nature communications 84 30890702
2016 TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities. Cell reports 82 27160912
2017 TET2 in Normal and Malignant Hematopoiesis. Cold Spring Harbor perspectives in medicine 78 28242787
2022 TET2 regulates osteoclastogenesis by modulating autophagy in OVX-induced bone loss. Autophagy 77 35255774
2020 Divergent Effects of Dnmt3a and Tet2 Mutations on Hematopoietic Progenitor Cell Fitness. Stem cell reports 77 32220332
2023 Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes. Nature cardiovascular research 76 39196062
2020 Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity. Nature immunology 76 32572241
2012 TET2 is essential for survival and hematopoietic stem cell homeostasis. Leukemia 74 22469782
2024 Colchicine prevents accelerated atherosclerosis in TET2-mutant clonal haematopoiesis. European heart journal 70 39212933
2023 BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis. Circulation 70 37781816
2016 TET2 binds the androgen receptor and loss is associated with prostate cancer. Oncogene 69 27819678
2020 Tet2 at the interface between cancer and immunity. Communications biology 68 33184433
2019 Specific functions of TET1 and TET2 in regulating mesenchymal cell lineage determination. Epigenetics & chromatin 68 30606231
2024 RNA m5C oxidation by TET2 regulates chromatin state and leukaemogenesis. Nature 64 39358506
2020 Age-Associated TET2 Mutations: Common Drivers of Myeloid Dysfunction, Cancer and Cardiovascular Disease. International journal of molecular sciences 62 31963585
2023 Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis. Nature cardiovascular research 61 37539077
2020 TET2 chemically modifies tRNAs and regulates tRNA fragment levels. Nature structural & molecular biology 61 33230319
2022 Tet2 deficiency drives liver microbiome dysbiosis triggering Tc1 cell autoimmune hepatitis. Cell host & microbe 58 35658976
2023 Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils. Cell stem cell 52 37267914
2019 Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis. Cancer discovery 51 30944118
2015 Tet1 and Tet2 Protect DNA Methylation Canyons against Hypermethylation. Molecular and cellular biology 51 26598602
2016 DNMT3A and TET2 in the Pre-Leukemic Phase of Hematopoietic Disorders. Frontiers in oncology 49 27597933
2022 Vitamin D receptor, STAT3, and TET2 cooperate to establish tolerogenesis. Cell reports 47 35045292
2020 Ascorbic Acid Promotes Plasma Cell Differentiation through Enhancing TET2/3-Mediated DNA Demethylation. Cell reports 47 33264617
2016 Dysregulation of TET2 in hematologic malignancies. International journal of hematology 45 27848178
2020 TET2 directs mammary luminal cell differentiation and endocrine response. Nature communications 43 32934200
2018 B-cell tumor development in Tet2-deficient mice. Blood advances 43 29581109
2016 Roles of IDH1/2 and TET2 mutations in myeloid disorders. International journal of hematology 42 26980223
2014 Identification of a melanoma susceptibility locus and somatic mutation in TET2. Carcinogenesis 40 24980573
2024 Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1. JAMA cardiology 39 38598228
2022 Ascorbic acid induced TET2 enzyme activation enhances cancer immunotherapy efficacy in renal cell carcinoma. International journal of biological sciences 39 35173532
2018 TET2: A Novel Epigenetic Regulator and Potential Intervention Target for Atherosclerosis. DNA and cell biology 39 29653065
2019 Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation. Epigenetics & chromatin 38 31164154
2018 TET2 facilitates PPARγ agonist-mediated gene regulation and insulin sensitization in adipocytes. Metabolism: clinical and experimental 37 30193945
2021 Tet2 Inactivation Enhances the Antitumor Activity of Tumor-Infiltrating Lymphocytes. Cancer research 36 33589517
2020 TET2: A cornerstone in normal and malignant hematopoiesis. Cancer science 34 33048426
2023 Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation. Nature communications 33 36737440
2022 How Human TET2 Enzyme Catalyzes the Oxidation of Unnatural Cytosine Modifications in Double-Stranded DNA. ACS catalysis 32 36339349
2023 TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells. Nature aging 31 37884767
2015 The TET2 interactors and their links to hematological malignancies. IUBMB life 31 26099018
2021 PROSER1 mediates TET2 O-GlcNAcylation to regulate DNA demethylation on UTX-dependent enhancers and CpG islands. Life science alliance 30 34667079
2020 TET2-mediated Cdkn2A DNA hydroxymethylation in midbrain dopaminergic neuron injury of Parkinson's disease. Human molecular genetics 28 32037456
2018 PML Recruits TET2 to Regulate DNA Modification and Cell Proliferation in Response to Chemotherapeutic Agent. Cancer research 28 29735542
2018 ETV2-TET1/TET2 Complexes Induce Endothelial Cell-Specific Robo4 Expression via Promoter Demethylation. Scientific reports 26 29618782
2017 TET2 mutation in diffuse large B-cell lymphoma. Journal of clinical and experimental hematopathology : JCEH 26 28331128
2018 TET2-Dependent Hydroxymethylome Plasticity Reduces Melanoma Initiation and Progression. Cancer research 25 30538121
2024 Experimental TET2 Clonal Hematopoiesis Predisposes to Renal Hypertension Through an Inflammasome-Mediated Mechanism. Circulation research 24 39234670
2023 Vitamin C boosts DNA demethylation in TET2 germline mutation carriers. Clinical epigenetics 24 36639817
2024 Association of Somatic TET2 Mutations With Giant Cell Arteritis. Arthritis & rheumatology (Hoboken, N.J.) 23 37909388
2021 Role of Tet2 in Regulating Adaptive and Innate Immunity. Frontiers in cell and developmental biology 23 34222235
2016 TET2-mediated 5-hydroxymethylcytosine induces genetic instability and mutagenesis. DNA repair 22 27289557
2023 TET2 and TET3 loss disrupts small intestine differentiation and homeostasis. Nature communications 21 37414790
2022 Loss of neuronal Tet2 enhances hippocampal-dependent cognitive function. Cell reports 21 36351399
2020 Analysis of TET2 and EZH2 gene functions in chromosome instability in acute myeloid leukemia. Scientific reports 21 32066746
2023 Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells. Proceedings of the National Academy of Sciences of the United States of America 20 36652477
2022 Dissecting TET2 Regulatory Networks in Blood Differentiation and Cancer. Cancers 20 35159097
2024 Tet methylcytosine dioxygenase 2 (TET2) deficiency elicits EGFR-TKI (tyrosine kinase inhibitors) resistance in non-small cell lung cancer. Signal transduction and targeted therapy 18 38461173
2024 TET2-STAT3-CXCL5 nexus promotes neutrophil lipid transfer to fuel lung adeno-to-squamous transition. The Journal of experimental medicine 18 38805014
2023 TET2 is required to suppress mTORC1 signaling through urea cycle with therapeutic potential. Cell discovery 18 37550284
2015 TET2 Mutation in Adult T-Cell Leukemia/Lymphoma. Journal of clinical and experimental hematopathology : JCEH 18 26763362
2024 TET2 mutation in acute myeloid leukemia: biology, clinical significance, and therapeutic insights. Clinical epigenetics 16 39521964
2021 DNA demethylase Tet2 suppresses cisplatin-induced acute kidney injury. Cell death discovery 16 34226503
2017 A role for TET2 in parathyroid carcinoma. Endocrine-related cancer 16 28642344
2022 ROS attenuates TET2-dependent ZO-1 epigenetic expression in cerebral vascular endothelial cells. Fluids and barriers of the CNS 15 36076297
2019 Endogenous epitope-tagging of Tet1, Tet2 and Tet3 identifies TET2 as a naïve pluripotency marker. Life science alliance 15 31582397
2024 TET2 mutation as prototypic clonal hematopoiesis lesion. Seminars in hematology 14 38431463
2024 A negative feedback loop between TET2 and leptin in adipocyte regulates body weight. Nature communications 14 38561362
2022 Clinical Significance of TET2 in Female Cancers. Frontiers in bioengineering and biotechnology 14 35223782
2016 Expression of TET2 enzyme indicates enhanced epigenetic modification of cells in periodontitis. European journal of oral sciences 14 27297088
2024 TET2-mediated ECM1 hypomethylation promotes the neovascularization in active proliferative diabetic retinopathy. Clinical epigenetics 13 38172938
2023 Endothelial TET2 regulates the white adipose browning and metabolism via fatty acid oxidation in obesity. Redox biology 13 38168657
2022 Physioxia-induced downregulation of Tet2 in hematopoietic stem cells contributes to enhanced self-renewal. Blood 13 35772013
2020 TET2 is involved in DNA hydroxymethylation, cell proliferation and inflammatory response in keratinocytes. Molecular medicine reports 13 32319620
2024 Tet2 modulates M2 macrophage polarization via mRNA 5-methylcytosine in allergic rhinitis. International immunopharmacology 12 39486186
2023 Tet2 regulates Sin3a recruitment at active enhancers in embryonic stem cells. iScience 12 37456851
2023 TET2 lesions enhance the aggressiveness of CEBPA-mutant acute myeloid leukemia by rebalancing GATA2 expression. Nature communications 12 37794021

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