{"gene":"KDM6B","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"JMJD3 (KDM6B) catalyzes demethylation of tri-methylated H3K27 (H3K27me3). Ectopic expression of JMJD3 causes a strong decrease of H3K27me3 levels and delocalization of polycomb proteins in vivo. The C. elegans ortholog F18E9.5 is required for gonad development.","method":"In vitro demethylase assay, ectopic expression in cells with H3K27me3 immunostaining, C. elegans RNAi/mutation","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic activity demonstrated, replicated across multiple organisms and labs, foundational paper","pmids":["17713478"],"is_preprint":false},{"year":2013,"finding":"Jmjd3 inhibits somatic cell reprogramming through two distinct mechanisms: (1) a demethylase-dependent pathway upregulating the INK4a/Arf locus, and (2) a demethylase-independent pathway in which Jmjd3 recruits E3 ubiquitin ligase Trim26 to target PHF20 for ubiquitination and degradation.","method":"iPSC reprogramming assays in wild-type vs. Jmjd3-deficient MEFs, ectopic expression, Co-IP, ubiquitination assays, catalytically inactive mutant controls","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination, catalytic mutant, genetic KO), demonstrated both demethylase-dependent and -independent mechanisms","pmids":["23452852"],"is_preprint":false},{"year":2012,"finding":"KDM6B promotes TGF-β-induced epithelial-mesenchymal transition (EMT) in mammary epithelial cells by demethylating H3K27me3 at the SNAI1 promoter, stimulating SNAI1 expression. KDM6B is induced by TGF-β and its knockdown inhibits EMT and breast cancer cell invasion.","method":"KDM6B knockdown and overexpression, ChIP assay for H3K27me3 at SNAI1 promoter, invasion assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with ChIP validation, single lab","pmids":["23152497"],"is_preprint":false},{"year":2012,"finding":"KDM6B promotes RNA Polymerase II progression along gene bodies of TGF-β-responsive genes by demethylating H3K27me3 in intragenic regions, thereby facilitating transcriptional elongation rather than only initiation.","method":"ChIP-seq for JMJD3, elongating RNAPII (Ser2-phospho), and H3K27me3 upon TGF-β treatment; genome-wide analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genome-wide ChIP-seq with mechanistic follow-up demonstrating co-localization of JMJD3 and elongating RNAPII in gene bodies","pmids":["23243002"],"is_preprint":false},{"year":2013,"finding":"Jmjd3 is required for mesoderm and subsequent cardiovascular lineage commitment in mouse embryonic stem cells. Jmjd3 reduces H3K27me3 marks at the Brachyury promoter and facilitates recruitment of β-catenin, which is critical for Wnt signal-induced mesoderm differentiation.","method":"Jmjd3 ablation in mouse ESCs, ChIP for H3K27me3 at Brachyury promoter, β-catenin recruitment assay","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with ChIP validation and β-catenin recruitment, single lab","pmids":["23856522"],"is_preprint":false},{"year":2013,"finding":"KDM6B and EED (PRC2 component) coordinately regulate the first mammalian cell lineage commitment. The relative levels of EED and KDM6B determine PRC2 recruitment and H3K27me3 status at CDX2 and GATA3 chromatin domains, leading to their activation in trophectoderm (TE) and repression in inner cell mass (ICM). Ectopic EED gain plus KDM6B depletion abrogates CDX2/GATA3 expression in TE and causes failure of embryo implantation.","method":"Genetic manipulation in preimplantation mouse embryos, ChIP for H3K27me3 at CDX2/GATA3 loci, phenotypic analysis of implantation failure","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in embryos with ChIP validation, single lab","pmids":["23671187"],"is_preprint":false},{"year":2014,"finding":"JMJD3 physically interacts with the tumor suppressor p53 (interaction dependent on the p53 tetramerization domain). Following DNA damage, JMJD3 is recruited to p53-bound promoters and enhancer elements in a p53-dependent manner, as demonstrated by genome-wide JMJD3 mapping showing significant overlap with p53 binding sites.","method":"Co-immunoprecipitation, ChIP-seq genome-wide mapping of JMJD3 and p53, p53 expression-dependent recruitment assay after DNA damage","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus genome-wide ChIP-seq, single lab","pmids":["24797517"],"is_preprint":false},{"year":2015,"finding":"Jmjd3-catalyzed removal of H3K27me3 is required for brown adipose tissue (BAT)-selective gene expression and development of beige adipocytes. Jmjd3 is recruited in part through the transcription factor Rreb1. Gain- and loss-of-function Jmjd3 transgenic mice show age-dependent body weight changes and cold intolerance, respectively.","method":"H3K27me3 ChIP-seq in brown/white preadipocytes, Jmjd3 gain/loss-of-function in vitro and transgenic mice, Rreb1-mediated recruitment assay","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq, multiple in vitro and in vivo models, transcription factor recruitment assay, replicated findings","pmids":["26625958"],"is_preprint":false},{"year":2016,"finding":"JMJD3 physically interacts with NF-κB and cooperates with it to induce expression of inflammatory, matrix metalloproteinase, and growth factor genes via demethylation of H3K27me3 at their promoters during keratinocyte wound healing. Inactivation of either JMJD3 or NF-κB impairs keratinocyte wound healing.","method":"Co-immunoprecipitation of JMJD3 and NF-κB, ChIP for H3K27me3 at target gene promoters, JMJD3/NF-κB inactivation in vitro and in vivo wound models","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus functional KO, single lab","pmids":["26802933"],"is_preprint":false},{"year":2016,"finding":"ISL1 physically interacts with JMJD3 and recruits it to enhancers of cardiac transcription factor genes (Myocd and Mef2c) to demethylate H3K27me3. ISL1 also modulates JMJD3's demethylase activity. Conditional depletion of JMJD3 impairs cardiac progenitor cell differentiation, phenocopying ISL1 depletion.","method":"Co-immunoprecipitation of ISL1 and JMJD3, ChIP for H3K27me3 at Myocd/Mef2c enhancers, conditional JMJD3 depletion in cardiac progenitors","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and genetic depletion phenotype in single lab with multiple methods","pmids":["27105846"],"is_preprint":false},{"year":2017,"finding":"KDM6B regulates multiple myeloma cell growth via a demethylase-independent mechanism: KDM6B is recruited to MAPK pathway gene loci (including ELK1 and FOS) and upregulates their expression without affecting H3K27 methylation levels. Overexpression of catalytically inactive KDM6B similarly activates MAPK pathway genes. KDM6B is regulated by NF-κB signaling in MM cells.","method":"shRNA knockdown, CRISPR KO, RNA-seq, ChIP-qPCR, overexpression of catalytically inactive KDM6B mutant, IKKβ inhibitor treatment","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — catalytic dead mutant overexpression combined with ChIP-qPCR and RNA-seq definitively establishes demethylase-independent transcriptional activation","pmids":["28487543"],"is_preprint":false},{"year":2017,"finding":"JMJD3 and NF-κB activate Notch1 transcription in wounded keratinocytes by removing H3K27me3 at the Notch1 promoter. Notch1 in turn activates RhoU and PLAU, which regulate filopodia formation and cell migration for skin wound healing.","method":"ChIP for H3K27me3 at Notch1 promoter, JMJD3/NF-κB depletion, Notch1 depletion with migration/filopodia assays in vitro and in vivo wound models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus genetic depletion with defined phenotypic readout, single lab","pmids":["28747631"],"is_preprint":false},{"year":2018,"finding":"JMJD3 forms a positive autoregulatory loop with SIRT1 and PPARα upon fasting-induced PKA signaling to epigenetically activate mitochondrial fatty acid β-oxidation genes (Fgf21, Cpt1a, Mcad) by removing H3K27me3. JMJD3 acts as a gene-specific transcriptional partner of SIRT1 selectively on β-oxidation genes but not gluconeogenic genes. Liver-specific knockdown of JMJD3 causes β-oxidation defects and hepatosteatosis.","method":"Co-immunoprecipitation of JMJD3/SIRT1/PPARα, ChIP for H3K27me3 at β-oxidation gene promoters, liver-specific JMJD3 knockdown, metabolic phenotyping","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP, liver-specific KD with metabolic phenotype, multiple orthogonal methods in one study","pmids":["29911994"],"is_preprint":false},{"year":2018,"finding":"JMJD3 promotes cardiac hypertrophy through a demethylase-dependent mechanism: JMJD3 is recruited to the β-MHC promoter, demethylates H3K27me3, and promotes β-MHC expression. Overexpression of wild-type but not demethylase-defective mutant JMJD3 promotes cardiomyocyte hypertrophy.","method":"Overexpression of WT vs. demethylase-defective JMJD3, ChIP for H3K27me3 at β-MHC promoter, isoproterenol-induced hypertrophy model, GSK-J4 inhibitor treatment","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — catalytic mutant establishes demethylase-dependence, ChIP validation, single lab","pmids":["29753027"],"is_preprint":false},{"year":2018,"finding":"JMJD3 promotes ABC-subtype DLBCL survival by demethylase-dependent upregulation of IRF4, which reciprocally stimulates JMJD3 expression, forming a positive feedback loop.","method":"JMJD3 silencing in DLBCL subtypes, IRF4 rescue experiments, demethylase activity-dependent assays, in vivo siRNA tumor treatment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — demethylase activity-dependent assay, rescue experiment, in vivo validation, single lab","pmids":["27102442"],"is_preprint":false},{"year":2018,"finding":"JMJD3 facilitates myeloid differentiation of AML cells via a physical and functional association with transcription factor C/EBPβ. JMJD3 modulates H3K4 and H3K27 methylation levels to activate myelopoietic regulatory genes, exerting an oncorepressor effect in M2/M3 AML subtypes.","method":"RNA-seq, ChIP-PCR, co-immunoprecipitation of JMJD3 and C/EBPβ, JMJD3 overexpression/knockdown in AML cell lines","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNA-seq, and ChIP-PCR in single lab","pmids":["30135572"],"is_preprint":false},{"year":2019,"finding":"JMJD3 regulates CD4+ T cell trafficking by activating Pdlim4 transcription through binding to the Pdlim4 promoter and gene body in cooperation with the zinc finger transcription factor KLF2. PDLIM4 acts as an adaptor between S1P1 and F-actin to enable T cell egress. JMJD3 deficiency leads to T cell accumulation in the thymus.","method":"Gene expression profiling and ChIP-seq in JMJD3-deficient CD4+ T cells, Co-IP of JMJD3 and KLF2, S1P1/F-actin interaction assays, in vivo T cell trafficking analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq, Co-IP, in vivo genetic model, and pathway placement with multiple orthogonal methods","pmids":["31393857"],"is_preprint":false},{"year":2019,"finding":"KDM6B is required for hematopoietic stem cell (HSC) self-renewal under inflammatory and proliferative stress. Loss of Kdm6b leads to a pro-differentiation state in HSCs due to increased expression of AP-1 complex (Fos/Jun) and IER genes independently of chromatin modifications. Targeting AP-1 restores Kdm6b-deficient HSC function.","method":"Conditional Kdm6b KO in mice, HSC functional assays, RNA-seq, AP-1 targeting rescue experiments","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with epistasis rescue, RNA-seq, chromatin-independent mechanism established, single lab","pmids":["30936419"],"is_preprint":false},{"year":2020,"finding":"JMJD3 is specifically recruited by KLF4 during reprogramming to reduce H3K27me3 at enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL, and drives transcriptional elongation. Simultaneously, JMJD3 induces Ink4a and degrades PHF20 (via Trim26) in a KLF4-independent manner.","method":"ChIP-seq for H3K27me3 and JMJD3 during reprogramming, Co-IP of JMJD3-KLF4 and JMJD3-NIPBL, enhancer-promoter looping analysis, Trim26-mediated PHF20 degradation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, Co-IP, looping, degradation assays) establishing multiple mechanistic arms","pmids":["33033262"],"is_preprint":false},{"year":2020,"finding":"STAT3 binds the Jmjd3 promoter and represses Jmjd3 transcription in glioblastoma stem cells. STAT3 inhibition upregulates JMJD3, which demethylates H3K27 at differentiation gene promoters (Myt1, FGF21, GDF15), slows glioblastoma stem cell growth, and Jmjd3 knockdown rescues STAT3 inhibitor-induced neurosphere formation defects.","method":"STAT3 ChIP at Jmjd3 promoter, JMJD3 overexpression/knockdown, H3K27 demethylation ChIP at differentiation gene promoters, neurosphere assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — STAT3 ChIP, H3K27 ChIP, genetic rescue, single lab","pmids":["28384648"],"is_preprint":false},{"year":2020,"finding":"In reptilian temperature-dependent sex determination, STAT3 phosphorylated at the female-producing temperature binds the Kdm6b locus and represses Kdm6b transcription, blocking the male developmental pathway. Ca2+ influx elevated at female temperature mediates STAT3 phosphorylation as a temperature-sensitive regulator.","method":"ChIP for pSTAT3 at Kdm6b locus, Ca2+ manipulation, STAT3 phosphorylation assays in turtle embryos at different temperatures","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct pSTAT3 binding at Kdm6b locus with causal Ca2+/STAT3 signaling established, single study","pmids":["32299951"],"is_preprint":false},{"year":2021,"finding":"JMJD3 (but not UTX) removes H3K27me3 marks at the Has2 locus in muscle stem cells to initiate hyaluronic acid (HA) production. This JMJD3-driven HA synthesis establishes an extracellular matrix enabling MuSCs to exit quiescence and overcome inhibitory inflammation during muscle regeneration.","method":"JMJD3/UTX-specific knockdown in MuSCs, ChIP for H3K27me3 at Has2 locus, HA production assays, in vitro and in vivo muscle regeneration models","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — paralog-specific comparison (JMJD3 vs UTX), ChIP at target locus, functional HA assay, in vivo validation","pmids":["35926054"],"is_preprint":false},{"year":2021,"finding":"KDM6B promotes CDK4/6-pRB-E2F oncogenic pathway in MYCN-amplified neuroblastoma via H3K27me3-dependent enhancer-promoter interactions: KDM6B inhibition reduces H3K27me3 but also decreases the enhancer mark H3K4me1 at CTCF/BORIS binding sites, disrupting long-range chromatin interactions of MYCN and E2F targets.","method":"KDM6B inhibition with GSK-J4, ATAC-seq for chromatin accessibility, H3K27me3/H3K4me1 ChIP, CDK4/6 overexpression and Rb1 KO resistance experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal chromatin assays (ATAC-seq, H3K27me3 ChIP, H3K4me1 ChIP), genetic rescue experiments, mechanistic pathway placement","pmids":["34893606"],"is_preprint":false},{"year":2021,"finding":"KDM6B mediates H3K27me3 demethylation at the LDHA promoter to upregulate LDHA expression in osteosarcoma cells, promoting aerobic glycolysis and lung metastasis. ChIP-seq and RNA-seq identified LDHA as a direct KDM6B target.","method":"ChIP-seq, RNA-seq, ChIP-qPCR for H3K27me3 at LDHA promoter, KDM6B knockdown with LDHA rescue, in vivo metastasis model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq, RNA-seq, and in vivo rescue experiment, single lab","pmids":["33664867"],"is_preprint":false},{"year":2021,"finding":"In macrophages, interferon-β regulates Jmjd3 expression via the JAK/STAT pathway, and JMJD3 induces NF-κB-mediated inflammatory gene transcription by removing repressive H3K27me3 marks from inflammatory gene promoters. Myeloid-specific Jmjd3 deletion preserved H3K27me3 at inflammatory gene promoters and reduced AAA expansion.","method":"Myeloid-specific Jmjd3 KO mice (Jmjd3f/fLyz2Cre+), single-cell RNA-seq of human AAA tissue, H3K27me3 ChIP at inflammatory gene promoters, pharmacological inhibition in elastase/angiotensin II AAA models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — myeloid-specific genetic KO with ChIP validation, single-cell transcriptomics, and in vivo disease model, multiple methods","pmids":["33779682"],"is_preprint":false},{"year":2021,"finding":"KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with Smad2/3 to promote cyclin D1 transcription in prostate cancer. Androgen receptor decreases KDM6B transcription, placing KDM6B downstream of androgen signaling.","method":"ChIP for H3K27me3 at cyclin D1 promoter, KDM6B overexpression/knockdown, Co-IP of KDM6B and Smad2/3, AR-KDM6B transcriptional regulation assay, in vivo xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, in vivo model, single lab","pmids":["33414463"],"is_preprint":false},{"year":2021,"finding":"KDM6B is recruited to the KDM6B locus by the SMAD2/3 complex downstream of activin A signaling in hippocampal neurons. Activin A treatment induces KDM6B expression via SMAD2/3 binding at the Kdm6b gene, conserved in human forebrain neurons.","method":"ChIP experiments with hippocampal lysates for SMAD2/3 binding at Kdm6b gene after electroconvulsive seizures, human ESC-derived forebrain neuron validation","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP in vivo and human cell validation, single lab","pmids":["26215835"],"is_preprint":false},{"year":2021,"finding":"KDM6B-dependent H3K27me3 demethylation is required for early CD8+ T cell differentiation: KDM6B is rapidly upregulated prior to the first cell division after naive T cell activation, enabling H3K27me3 removal at differentiation/proliferation genes. KDM6B inhibition limits the magnitude of primary virus-specific CD8+ T cell responses and memory formation.","method":"Genome-wide ATAC-seq, H3K27me3 ChIP-seq, RNA-seq, KDM6B inhibition during virus-specific T cell responses in vivo","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide chromatin accessibility, H3K27me3 ChIP-seq, and in vivo functional immune assays with multiple orthogonal methods","pmids":["33730567"],"is_preprint":false},{"year":2022,"finding":"KDM6B interacts with transcription factor TFDP1 to activate Trp53 expression during palatogenesis. Without KDM6B, TFDP1 cannot activate Trp53. Activity of H3K27me3 at the Trp53 promoter is antagonistically controlled by KDM6B and EZH2. KDM6A cannot compensate for KDM6B loss in this context.","method":"Conditional Kdm6b KO in cranial neural crest cells, ChIP for H3K27me3 at Trp53 promoter, Co-IP/interaction assays of KDM6B and TFDP1, rescue experiments with Kdm6a","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, ChIP, protein interaction, paralog rescue experiment, single lab","pmids":["35212626"],"is_preprint":false},{"year":2022,"finding":"KDM6B cooperates with Tau to regulate synaptic plasticity and cognition. Tau interacts with KDM6B and recruits it to the promoters of Slc17a7 (VGLUT1) and Slc17a6 (VGLUT2) in neurons, reducing local H3K27me3 and inducing VGLUT1/2 expression. Conditional KDM6B KO in excitatory neurons reduces spine density and impairs memory.","method":"Conditional KO in excitatory neurons, ChIP for H3K27me3 at VGLUT1/2 promoters, Co-IP of KDM6B and Tau, spine density/synaptic activity measurements, Tau KO loss-of-function rescue","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, conditional KO with behavioral and synaptic phenotypes, single lab","pmids":["36028572"],"is_preprint":false},{"year":2022,"finding":"KDM6B promotes PARthanatos (PARP-1-dependent cell death) in response to alkylating agents by suppressing MGMT expression: KDM6B knockout reduces H3K27me3 at the MGMT promoter, enhancing MGMT expression and direct DNA repair, thereby inhibiting PARP-1 hyperactivation. KDM6B KO also triggers sustained Chk1 phosphorylation activating a secondary XRCC1-dependent repair pathway.","method":"KDM6B KO, ChIP for H3K27me3 at MGMT promoter, PARP-1 hyperactivation assays, MGMT expression and DNA repair functional assays, Chk1 phosphorylation analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with ChIP, functional DNA repair assays, checkpoint signaling, single lab","pmids":["35648484"],"is_preprint":false},{"year":2022,"finding":"Kdm6b regulates motor neuron subtype diversification by working together with the transcription factor complex Isl1-Lhx3. Kdm6b promotes MMC and HMC fates while inhibiting LMC and PGC identities in mouse embryonic spinal cord. Single-cell RNA-seq demonstrated cell-type heterogeneity dependent on Kdm6b.","method":"Conditional Kdm6b KO in mouse embryonic motor neurons, single-cell RNA-seq, Isl1-Lhx3 complex interaction studies, motor column fate analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with scRNA-seq and transcription factor complex studies, single lab","pmids":["35177643"],"is_preprint":false},{"year":2022,"finding":"In the context of diabetic wound healing, IL-6 activates the JAK1,3/STAT3 pathway to regulate JMJD3 expression in diabetic wound macrophages. Late-elevated JMJD3 induces NFκB-mediated inflammatory transcription via H3K27me3 removal. JMJD3 also controls STING (Tmem173) gene expression in wound macrophages through an H3K27me3 mechanism.","method":"Myeloid-specific Jmjd3 KO mice, single-cell RNA-seq, RNA-seq of isolated wound macrophages, H3K27me3 ChIP, nanoparticle-mediated JMJD3 inhibition in diabetic wounds","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — myeloid-specific KO, scRNA-seq, H3K27me3 ChIP, in vivo therapeutic intervention, single lab","pmids":["36127466"],"is_preprint":false},{"year":2022,"finding":"IFNβ reduces the cellular α-ketoglutarate/succinate ratio by inhibiting isocitrate dehydrogenase and boosting succinate, which potently blocks the JMJD3-IRF4-dependent M2 macrophage polarization pathway. Supplementation with α-ketoglutarate reverses IFNβ-mediated suppression of JMJD3-IRF4 responses.","method":"Metabolic flux analysis (isotope tracing), α-ketoglutarate supplementation rescue, macrophage polarization assays, JMJD3-IRF4 pathway functional studies","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolic mechanism with rescue experiment, multiple cell-based assays, single lab","pmids":["35443173"],"is_preprint":false},{"year":2023,"finding":"Myeloid-specific Kdm6b deletion enhances antigen presentation, interferon response, and phagocytosis in myeloid cells by inhibiting mediators of immune suppression including Mafb, Socs3, and Sirpa. This reprogramming sensitizes glioblastoma to anti-PD1 immunotherapy. Pharmacological KDM6B inhibition mirrors the genetic Kdm6b deletion phenotype.","method":"Myeloid-specific Kdm6b KO mice with GBM tumor model, single-cell and spatial transcriptomics, mechanistic gene expression studies, anti-PD1 combination treatment in vivo","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — myeloid-specific genetic KO with comprehensive transcriptomics, pharmacological validation, in vivo immune checkpoint data, multiple methods","pmids":["37653141"],"is_preprint":false},{"year":2021,"finding":"The lncRNA DNM3OS physically interacts with KDM6B in the nucleus of HCC cells. This DNM3OS-KDM6B association reduces H3K27me3 at the TIAM1 promoter, inducing TIAM1 expression and promoting HCC metastasis.","method":"Nuclear localization and pulldown of DNM3OS-KDM6B interaction, ChIP for H3K27me3 at TIAM1 promoter, TIAM1 rescue experiments","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/pulldown with ChIP, single lab, lncRNA-protein interaction","pmids":["33472090"],"is_preprint":false},{"year":2021,"finding":"KDM6B functions as a coactivator of HIF-1α-mediated Nox4 transactivation in response to intermittent hypoxia (IH). KDM6B protein and enzyme activity are increased by IH independently of HIF-1α. KDM6B blockade abolishes HIF-1α binding to the Nox4 HRE promoter and prevents IH-induced hypertension in vivo.","method":"ChIP for HIF-1α binding at Nox4 HRE, KDM6B shRNA and pharmacological inhibition (GSKJ4), KDM6B enzyme activity assay, rat IH hypertension model","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, enzyme activity assay, shRNA KD, in vivo rat model, single lab","pmids":["34297635"],"is_preprint":false},{"year":2017,"finding":"Conditional deletion of Kdm6b (using Col2a1-CreER) in chondrocytes causes skeletal abnormalities and accelerated osteoarthritis via inhibition of chondrocyte anabolic gene expression. RNA-seq identified downregulation of anabolic chondrocyte genes in Kdm6b-deficient chondrocytes.","method":"Conditional Kdm6b KO in cartilage (Col2a1-CreER), RNA-seq, intra-articular shRNA lentiviral injection, OA histological scoring","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional genetic KO with RNA-seq, in vivo disease model, single lab","pmids":["28314754"],"is_preprint":false},{"year":2011,"finding":"KDM6B (JMJD3) expression is induced by the EBV oncogene LMP1 in germinal centre B cells. KDM6B depletion restores H3K27me3 trimethylation on KDM6B target genes in Hodgkin's lymphoma cells.","method":"LMP1 ectopic expression, KDM6B depletion, ChIP for H3K27me3 at KDM6B target gene loci","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP with genetic manipulation demonstrating LMP1→KDM6B→H3K27me3 axis, single lab","pmids":["21242977"],"is_preprint":false},{"year":2011,"finding":"JMJD3 expression is induced by 1,25(OH)2D3 in a VDR-dependent manner (abolished by cycloheximide, requiring new protein synthesis). JMJD3 modulates vitamin D receptor target gene expression; knockdown of JMJD3 or expression of an inactive mutant JMJD3 reduces 1,25(OH)2D3-induced gene activation and epithelial phenotype, and upregulates EMT inducers.","method":"JMJD3 promoter activation assays, VDR-dependent expression analysis, JMJD3 knockdown and inactive mutant expression, ChIP for H3K27me3 at VDR target gene promoters","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — catalytic mutant and ChIP analysis in VDR-dependent context, single lab","pmids":["21890490"],"is_preprint":false},{"year":2019,"finding":"KDM6B demethylates H3K27me3 at neuronal gene promoters to activate transcription during neuroblastoma differentiation. KDM6B expression is upregulated by retinoic acid via HOXC9. KDM6B physically interacts with HOXC9 to target neuronal genes for epigenetic activation, and is required for HOXC9-induced differentiation.","method":"ChIP for H3K27me3 at neuronal gene promoters, KDM6B overexpression/depletion, Co-IP of KDM6B and HOXC9, retinoic acid treatment","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, genetic manipulation with defined differentiation phenotype, single lab","pmids":["30631055"],"is_preprint":false},{"year":2024,"finding":"miR-93-5p targets the 3' UTR of KDM6B to inhibit its protein translation. KDM6B binds the BMP2 promoter and demethylates H3K27me3 marks to activate BMP2 transcription in dental pulp stem cells, promoting odontogenic differentiation and tertiary dentin formation.","method":"Dual luciferase reporter assay for miR-93-5p/KDM6B 3'UTR, ChIP-qPCR for KDM6B binding and H3K27me3 at BMP2 promoter, KDM6B overexpression in rat pulpotomy model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter, ChIP-qPCR, in vivo model validation, single lab","pmids":["38218880"],"is_preprint":false}],"current_model":"KDM6B (JMJD3) is an inducible histone H3K27me2/me3 demethylase that activates gene transcription by removing repressive polycomb marks at promoters, gene bodies, and enhancers; beyond its catalytic activity, it also operates through demethylase-independent mechanisms including recruitment of E3 ubiquitin ligase Trim26 to degrade PHF20, scaffolding enhancer-promoter looping via NIPBL, and coactivation of transcription factors such as NF-κB, C/EBPβ, ISL1, KLF4, KLF2, and HOXC9 in a context-dependent manner across development, immunity, metabolism, and disease."},"narrative":{"mechanistic_narrative":"KDM6B (JMJD3) is an inducible histone H3K27me2/me3 demethylase that activates gene transcription by removing repressive polycomb marks at promoters, gene bodies, and enhancers, thereby licensing context-dependent transcriptional programs across development, immunity, metabolism, and disease [PMID:17713478, PMID:23243002]. Its catalytic core converts H3K27me3 to lower methylation states, displacing polycomb proteins [PMID:17713478], and at TGF-β-responsive loci it acts not only at promoters but within gene bodies to facilitate elongating RNA Polymerase II progression [PMID:23243002]. KDM6B is overwhelmingly deployed as a recruited cofactor: sequence-specific transcription factors and signaling effectors—including NF-κB [PMID:26802933], C/EBPβ [PMID:30135572], ISL1 and the Isl1-Lhx3 complex [PMID:27105846, PMID:35177643], KLF2 [PMID:31393857], KLF4 [PMID:33033262], HOXC9 [PMID:30631055], Smad2/3 [PMID:33414463], TFDP1 [PMID:35212626], and p53 [PMID:24797517]—physically engage KDM6B and direct it to specific enhancers and promoters where it erases H3K27me3 to drive lineage commitment, T-cell trafficking and differentiation, myeloid and metabolic gene programs, and tumor-associated transcription. Beyond catalysis, KDM6B operates through demethylase-independent mechanisms: it recruits the E3 ligase Trim26 to ubiquitinate and degrade PHF20 [PMID:23452852, PMID:33033262], scaffolds enhancer-promoter looping via the cohesin loading factor NIPBL [PMID:33033262], and activates MAPK-pathway genes (ELK1, FOS) and pro-differentiation AP-1/IER programs in a chromatin-modification-independent manner [PMID:28487543, PMID:30936419]. KDM6B expression is itself a regulatory hub, induced or repressed by signaling inputs including TGF-β/activin-SMAD [PMID:23152497, PMID:26215835], interferon/JAK-STAT [PMID:28384648, PMID:32299951, PMID:33779682], vitamin D/VDR [PMID:21890490], and microRNA targeting [PMID:38218880], positioning it as a signal-responsive switch that couples extracellular cues to polycomb-controlled gene activation.","teleology":[{"year":2007,"claim":"Established the founding biochemical identity of KDM6B, answering whether it is an enzyme acting on chromatin and showing it actively reverses a repressive polycomb mark.","evidence":"In vitro demethylase assay, ectopic expression with H3K27me3 immunostaining, and C. elegans ortholog genetics","pmids":["17713478"],"confidence":"High","gaps":["Did not define which transcription factors target the enzyme to specific loci","No structural basis for substrate selectivity"]},{"year":2011,"claim":"Connected KDM6B to upstream signaling and oncogenic induction, showing its expression is driven by VDR and the EBV oncogene LMP1 to control polycomb status at target genes.","evidence":"VDR-dependent induction with catalytic mutant and ChIP; LMP1 ectopic expression with H3K27me3 ChIP in lymphoma cells","pmids":["21890490","21242977"],"confidence":"Medium","gaps":["Did not map the full target gene set","Mechanism of locus-specific recruitment not resolved"]},{"year":2012,"claim":"Defined the dual transcriptional logic of KDM6B in TGF-β responses—activating SNAI1 to drive EMT and acting within gene bodies to enable RNAPII elongation, not just initiation.","evidence":"Knockdown/overexpression with promoter ChIP and invasion assays; genome-wide ChIP-seq for JMJD3, elongating RNAPII, and H3K27me3","pmids":["23152497","23243002"],"confidence":"High","gaps":["How JMJD3 couples to elongation machinery mechanistically not defined","EMT findings from a single lab"]},{"year":2013,"claim":"Revealed that KDM6B acts both catalytically and non-catalytically, including a demethylase-independent arm recruiting Trim26 to degrade PHF20, and showed it balances PRC2 to set lineage fates.","evidence":"iPSC reprogramming in Jmjd3-deficient MEFs with Co-IP, ubiquitination assays, catalytic mutants; embryo genetic manipulation with H3K27me3 ChIP at lineage loci; ESC mesoderm differentiation assays","pmids":["23452852","23671187","23856522"],"confidence":"High","gaps":["How KDM6B selects PHF20 versus other substrates for Trim26 unclear","Stoichiometry of KDM6B vs PRC2 in fate decisions not quantified"]},{"year":2016,"claim":"Generalized KDM6B as a recruited transcription-factor cofactor by showing direct physical partnerships with NF-κB, ISL1, and p53 that target it to specific enhancers and promoters.","evidence":"Co-IP and ChIP/ChIP-seq with functional inactivation in keratinocyte wound healing, cardiac progenitors, and DNA-damage responses","pmids":["26802933","27105846","24797517"],"confidence":"Medium","gaps":["Whether these interactions are direct or bridged is not always resolved","Domain requirements for each partnership incompletely mapped"]},{"year":2017,"claim":"Demonstrated catalysis-independent transcriptional activation as a bona fide mechanism, showing catalytically dead KDM6B still activates MAPK genes, and extended KDM6B roles to chondrocyte anabolism.","evidence":"CRISPR KO, RNA-seq, ChIP-qPCR and catalytically inactive mutant overexpression in myeloma; conditional cartilage KO with RNA-seq and OA models","pmids":["28487543","28314754"],"confidence":"High","gaps":["The chromatin-independent effector mechanism on MAPK loci not defined","How KDM6B activates genes without modifying H3K27 is unresolved"]},{"year":2018,"claim":"Mapped KDM6B into metabolic and disease-specific transcriptional circuits, partnering with SIRT1/PPARα, IRF4, and C/EBPβ in feedback loops controlling β-oxidation, lymphoma survival, and myeloid differentiation.","evidence":"Co-IP, ChIP, liver-specific knockdown with metabolic phenotyping; demethylase-dependent rescue assays in DLBCL; Co-IP/RNA-seq/ChIP in AML","pmids":["29911994","27102442","30135572","29753027"],"confidence":"Medium","gaps":["Gene-specificity determinants of SIRT1 partnership not defined","Whether feedback loops generalize beyond the studied systems unknown"]},{"year":2020,"claim":"Integrated the multiple mechanistic arms of KDM6B during reprogramming, showing KLF4-directed enhancer demethylation, NIPBL-dependent enhancer-promoter looping, elongation, and parallel PHF20 degradation.","evidence":"ChIP-seq for JMJD3/H3K27me3, Co-IP of JMJD3-KLF4 and JMJD3-NIPBL, looping analysis, and Trim26-PHF20 degradation assays during reprogramming","pmids":["33033262"],"confidence":"High","gaps":["How NIPBL recruitment is mechanistically achieved by KDM6B is unresolved","Relative contribution of each arm to reprogramming not partitioned"]},{"year":2021,"claim":"Expanded KDM6B into chromatin-architecture and stress-adaptive immune/metabolic programs, including paralog-specific (vs UTX) action at Has2, enhancer-looping in neuroblastoma, glycolytic LDHA control, and CD8+ T cell priming.","evidence":"Paralog-specific knockdown with ChIP and HA assays; ATAC-seq and H3K4me1/H3K27me3 ChIP with genetic rescue in neuroblastoma; ChIP-seq/RNA-seq in osteosarcoma; ATAC-seq/H3K27me3 ChIP-seq/RNA-seq in T cells","pmids":["35926054","34893606","33664867","33730567"],"confidence":"High","gaps":["Basis of JMJD3 vs UTX functional specialization unknown","How KDM6B influences H3K4me1 and CTCF/BORIS-dependent looping mechanistically unresolved"]},{"year":2022,"claim":"Consolidated KDM6B as a recruited partner across diverse tissues—TFDP1 in palatogenesis, Tau in neurons, Isl1-Lhx3 in motor neurons, and macrophage inflammatory programs—and linked it to DNA-repair-coupled cell death.","evidence":"Conditional KOs with ChIP, Co-IP, scRNA-seq, behavioral/synaptic readouts, and MGMT/PARP-1 DNA repair assays","pmids":["35212626","36028572","35177643","36127466","35648484","35443173"],"confidence":"Medium","gaps":["Why paralog KDM6A cannot compensate in several contexts is unexplained","Direct versus indirect nature of the Tau interaction not fully resolved"]},{"year":2023,"claim":"Established KDM6B as a therapeutic target in tumor immunity, showing myeloid-specific deletion reprograms suppressive myeloid cells and sensitizes glioblastoma to checkpoint blockade.","evidence":"Myeloid-specific Kdm6b KO with GBM models, single-cell and spatial transcriptomics, pharmacological inhibition, and anti-PD1 combination in vivo","pmids":["37653141"],"confidence":"High","gaps":["Direct KDM6B targets driving Mafb/Socs3/Sirpa suppression not pinpointed","Whether effects are demethylase-dependent not fully partitioned"]},{"year":2024,"claim":"Extended upstream regulation of KDM6B to microRNA control, showing miR-93-5p represses KDM6B translation while KDM6B activates BMP2 to drive odontogenic differentiation.","evidence":"Dual luciferase reporter, ChIP-qPCR at BMP2 promoter, and in vivo pulpotomy model","pmids":["38218880"],"confidence":"Medium","gaps":["Broader miRNA regulatory network for KDM6B not mapped","Single-lab validation"]},{"year":null,"claim":"It remains unresolved how KDM6B's catalytic and non-catalytic activities are selected and balanced at individual loci, and what structural features dictate its partner- and paralog-specific recruitment.","evidence":"No single study in the corpus resolves the determinants of catalytic versus scaffold function genome-wide","pmids":[],"confidence":"Low","gaps":["No structural model explaining partner-specific recruitment","Determinants of demethylase-dependent vs -independent gene activation undefined","Mechanism distinguishing KDM6B from KDM6A/UTX at shared loci unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,21]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[10,16,18]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,9,25,36,40]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,35]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,18]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,3,18]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,10,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[24,27,34]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,5,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,25]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,12,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[14,22,34]}],"complexes":[],"partners":["TRIM26","PHF20","NIPBL","KLF4","ISL1","NFKB1","CEBPB","SMAD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15054","full_name":"Lysine-specific demethylase 6B","aliases":["JmjC domain-containing protein 3","Jumonji domain-containing protein 3","Lysine demethylase 6B","[histone H3]-trimethyl-L-lysine(27) demethylase 6B"],"length_aa":1643,"mass_kda":176.6,"function":"Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code (PubMed:17713478, PubMed:17825402, PubMed:17851529, PubMed:18003914). Demethylates trimethylated and dimethylated H3 'Lys-27' (PubMed:17713478, PubMed:17825402, PubMed:17851529, PubMed:18003914). Plays a central role in regulation of posterior development, by regulating HOX gene expression (PubMed:17851529). Involved in inflammatory response by participating in macrophage differentiation in case of inflammation by regulating gene expression and macrophage differentiation (PubMed:17825402). Plays a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression by acting as a link between T-box factors and the SMARCA4-containing SWI/SNF remodeling complex (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O15054/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM6B","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KDM6B","total_profiled":1310},"omim":[{"mim_id":"618505","title":"STOLERMAN NEURODEVELOPMENTAL SYNDROME; NEDSST","url":"https://www.omim.org/entry/618505"},{"mim_id":"614341","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 33; MRT33","url":"https://www.omim.org/entry/614341"},{"mim_id":"613065","title":"LEUKEMIA, ACUTE LYMPHOBLASTIC; ALL","url":"https://www.omim.org/entry/613065"},{"mim_id":"611577","title":"LYSINE DEMETHYLASE 6B; KDM6B","url":"https://www.omim.org/entry/611577"},{"mim_id":"606496","title":"INTERLEUKIN 17F; IL17F","url":"https://www.omim.org/entry/606496"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM6B"},"hgnc":{"alias_symbol":["KIAA0346"],"prev_symbol":["JMJD3"]},"alphafold":{"accession":"O15054","domains":[{"cath_id":"1.25.40.10","chopping":"93-154","consensus_level":"medium","plddt":89.2287,"start":93,"end":154},{"cath_id":"2.60.120.650","chopping":"1170-1294_1324-1488","consensus_level":"medium","plddt":96.6895,"start":1170,"end":1488}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15054","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15054-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15054-F1-predicted_aligned_error_v6.png","plddt_mean":57.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM6B","jax_strain_url":"https://www.jax.org/strain/search?query=KDM6B"},"sequence":{"accession":"O15054","fasta_url":"https://rest.uniprot.org/uniprotkb/O15054.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15054/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15054"}},"corpus_meta":[{"pmid":"17713478","id":"PMC_17713478","title":"UTX 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Ectopic expression of JMJD3 causes a strong decrease of H3K27me3 levels and delocalization of polycomb proteins in vivo. The C. elegans ortholog F18E9.5 is required for gonad development.\",\n      \"method\": \"In vitro demethylase assay, ectopic expression in cells with H3K27me3 immunostaining, C. elegans RNAi/mutation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic activity demonstrated, replicated across multiple organisms and labs, foundational paper\",\n      \"pmids\": [\"17713478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jmjd3 inhibits somatic cell reprogramming through two distinct mechanisms: (1) a demethylase-dependent pathway upregulating the INK4a/Arf locus, and (2) a demethylase-independent pathway in which Jmjd3 recruits E3 ubiquitin ligase Trim26 to target PHF20 for ubiquitination and degradation.\",\n      \"method\": \"iPSC reprogramming assays in wild-type vs. Jmjd3-deficient MEFs, ectopic expression, Co-IP, ubiquitination assays, catalytically inactive mutant controls\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination, catalytic mutant, genetic KO), demonstrated both demethylase-dependent and -independent mechanisms\",\n      \"pmids\": [\"23452852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM6B promotes TGF-β-induced epithelial-mesenchymal transition (EMT) in mammary epithelial cells by demethylating H3K27me3 at the SNAI1 promoter, stimulating SNAI1 expression. KDM6B is induced by TGF-β and its knockdown inhibits EMT and breast cancer cell invasion.\",\n      \"method\": \"KDM6B knockdown and overexpression, ChIP assay for H3K27me3 at SNAI1 promoter, invasion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with ChIP validation, single lab\",\n      \"pmids\": [\"23152497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM6B promotes RNA Polymerase II progression along gene bodies of TGF-β-responsive genes by demethylating H3K27me3 in intragenic regions, thereby facilitating transcriptional elongation rather than only initiation.\",\n      \"method\": \"ChIP-seq for JMJD3, elongating RNAPII (Ser2-phospho), and H3K27me3 upon TGF-β treatment; genome-wide analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genome-wide ChIP-seq with mechanistic follow-up demonstrating co-localization of JMJD3 and elongating RNAPII in gene bodies\",\n      \"pmids\": [\"23243002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jmjd3 is required for mesoderm and subsequent cardiovascular lineage commitment in mouse embryonic stem cells. Jmjd3 reduces H3K27me3 marks at the Brachyury promoter and facilitates recruitment of β-catenin, which is critical for Wnt signal-induced mesoderm differentiation.\",\n      \"method\": \"Jmjd3 ablation in mouse ESCs, ChIP for H3K27me3 at Brachyury promoter, β-catenin recruitment assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with ChIP validation and β-catenin recruitment, single lab\",\n      \"pmids\": [\"23856522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM6B and EED (PRC2 component) coordinately regulate the first mammalian cell lineage commitment. The relative levels of EED and KDM6B determine PRC2 recruitment and H3K27me3 status at CDX2 and GATA3 chromatin domains, leading to their activation in trophectoderm (TE) and repression in inner cell mass (ICM). Ectopic EED gain plus KDM6B depletion abrogates CDX2/GATA3 expression in TE and causes failure of embryo implantation.\",\n      \"method\": \"Genetic manipulation in preimplantation mouse embryos, ChIP for H3K27me3 at CDX2/GATA3 loci, phenotypic analysis of implantation failure\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in embryos with ChIP validation, single lab\",\n      \"pmids\": [\"23671187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"JMJD3 physically interacts with the tumor suppressor p53 (interaction dependent on the p53 tetramerization domain). Following DNA damage, JMJD3 is recruited to p53-bound promoters and enhancer elements in a p53-dependent manner, as demonstrated by genome-wide JMJD3 mapping showing significant overlap with p53 binding sites.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq genome-wide mapping of JMJD3 and p53, p53 expression-dependent recruitment assay after DNA damage\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus genome-wide ChIP-seq, single lab\",\n      \"pmids\": [\"24797517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Jmjd3-catalyzed removal of H3K27me3 is required for brown adipose tissue (BAT)-selective gene expression and development of beige adipocytes. Jmjd3 is recruited in part through the transcription factor Rreb1. Gain- and loss-of-function Jmjd3 transgenic mice show age-dependent body weight changes and cold intolerance, respectively.\",\n      \"method\": \"H3K27me3 ChIP-seq in brown/white preadipocytes, Jmjd3 gain/loss-of-function in vitro and transgenic mice, Rreb1-mediated recruitment assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq, multiple in vitro and in vivo models, transcription factor recruitment assay, replicated findings\",\n      \"pmids\": [\"26625958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"JMJD3 physically interacts with NF-κB and cooperates with it to induce expression of inflammatory, matrix metalloproteinase, and growth factor genes via demethylation of H3K27me3 at their promoters during keratinocyte wound healing. Inactivation of either JMJD3 or NF-κB impairs keratinocyte wound healing.\",\n      \"method\": \"Co-immunoprecipitation of JMJD3 and NF-κB, ChIP for H3K27me3 at target gene promoters, JMJD3/NF-κB inactivation in vitro and in vivo wound models\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus functional KO, single lab\",\n      \"pmids\": [\"26802933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ISL1 physically interacts with JMJD3 and recruits it to enhancers of cardiac transcription factor genes (Myocd and Mef2c) to demethylate H3K27me3. ISL1 also modulates JMJD3's demethylase activity. Conditional depletion of JMJD3 impairs cardiac progenitor cell differentiation, phenocopying ISL1 depletion.\",\n      \"method\": \"Co-immunoprecipitation of ISL1 and JMJD3, ChIP for H3K27me3 at Myocd/Mef2c enhancers, conditional JMJD3 depletion in cardiac progenitors\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and genetic depletion phenotype in single lab with multiple methods\",\n      \"pmids\": [\"27105846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM6B regulates multiple myeloma cell growth via a demethylase-independent mechanism: KDM6B is recruited to MAPK pathway gene loci (including ELK1 and FOS) and upregulates their expression without affecting H3K27 methylation levels. Overexpression of catalytically inactive KDM6B similarly activates MAPK pathway genes. KDM6B is regulated by NF-κB signaling in MM cells.\",\n      \"method\": \"shRNA knockdown, CRISPR KO, RNA-seq, ChIP-qPCR, overexpression of catalytically inactive KDM6B mutant, IKKβ inhibitor treatment\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — catalytic dead mutant overexpression combined with ChIP-qPCR and RNA-seq definitively establishes demethylase-independent transcriptional activation\",\n      \"pmids\": [\"28487543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD3 and NF-κB activate Notch1 transcription in wounded keratinocytes by removing H3K27me3 at the Notch1 promoter. Notch1 in turn activates RhoU and PLAU, which regulate filopodia formation and cell migration for skin wound healing.\",\n      \"method\": \"ChIP for H3K27me3 at Notch1 promoter, JMJD3/NF-κB depletion, Notch1 depletion with migration/filopodia assays in vitro and in vivo wound models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus genetic depletion with defined phenotypic readout, single lab\",\n      \"pmids\": [\"28747631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD3 forms a positive autoregulatory loop with SIRT1 and PPARα upon fasting-induced PKA signaling to epigenetically activate mitochondrial fatty acid β-oxidation genes (Fgf21, Cpt1a, Mcad) by removing H3K27me3. JMJD3 acts as a gene-specific transcriptional partner of SIRT1 selectively on β-oxidation genes but not gluconeogenic genes. Liver-specific knockdown of JMJD3 causes β-oxidation defects and hepatosteatosis.\",\n      \"method\": \"Co-immunoprecipitation of JMJD3/SIRT1/PPARα, ChIP for H3K27me3 at β-oxidation gene promoters, liver-specific JMJD3 knockdown, metabolic phenotyping\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP, liver-specific KD with metabolic phenotype, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29911994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD3 promotes cardiac hypertrophy through a demethylase-dependent mechanism: JMJD3 is recruited to the β-MHC promoter, demethylates H3K27me3, and promotes β-MHC expression. Overexpression of wild-type but not demethylase-defective mutant JMJD3 promotes cardiomyocyte hypertrophy.\",\n      \"method\": \"Overexpression of WT vs. demethylase-defective JMJD3, ChIP for H3K27me3 at β-MHC promoter, isoproterenol-induced hypertrophy model, GSK-J4 inhibitor treatment\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — catalytic mutant establishes demethylase-dependence, ChIP validation, single lab\",\n      \"pmids\": [\"29753027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD3 promotes ABC-subtype DLBCL survival by demethylase-dependent upregulation of IRF4, which reciprocally stimulates JMJD3 expression, forming a positive feedback loop.\",\n      \"method\": \"JMJD3 silencing in DLBCL subtypes, IRF4 rescue experiments, demethylase activity-dependent assays, in vivo siRNA tumor treatment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — demethylase activity-dependent assay, rescue experiment, in vivo validation, single lab\",\n      \"pmids\": [\"27102442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD3 facilitates myeloid differentiation of AML cells via a physical and functional association with transcription factor C/EBPβ. JMJD3 modulates H3K4 and H3K27 methylation levels to activate myelopoietic regulatory genes, exerting an oncorepressor effect in M2/M3 AML subtypes.\",\n      \"method\": \"RNA-seq, ChIP-PCR, co-immunoprecipitation of JMJD3 and C/EBPβ, JMJD3 overexpression/knockdown in AML cell lines\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNA-seq, and ChIP-PCR in single lab\",\n      \"pmids\": [\"30135572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JMJD3 regulates CD4+ T cell trafficking by activating Pdlim4 transcription through binding to the Pdlim4 promoter and gene body in cooperation with the zinc finger transcription factor KLF2. PDLIM4 acts as an adaptor between S1P1 and F-actin to enable T cell egress. JMJD3 deficiency leads to T cell accumulation in the thymus.\",\n      \"method\": \"Gene expression profiling and ChIP-seq in JMJD3-deficient CD4+ T cells, Co-IP of JMJD3 and KLF2, S1P1/F-actin interaction assays, in vivo T cell trafficking analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq, Co-IP, in vivo genetic model, and pathway placement with multiple orthogonal methods\",\n      \"pmids\": [\"31393857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM6B is required for hematopoietic stem cell (HSC) self-renewal under inflammatory and proliferative stress. Loss of Kdm6b leads to a pro-differentiation state in HSCs due to increased expression of AP-1 complex (Fos/Jun) and IER genes independently of chromatin modifications. Targeting AP-1 restores Kdm6b-deficient HSC function.\",\n      \"method\": \"Conditional Kdm6b KO in mice, HSC functional assays, RNA-seq, AP-1 targeting rescue experiments\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with epistasis rescue, RNA-seq, chromatin-independent mechanism established, single lab\",\n      \"pmids\": [\"30936419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD3 is specifically recruited by KLF4 during reprogramming to reduce H3K27me3 at enhancers and promoters of epithelial and pluripotency genes. JMJD3 also promotes enhancer-promoter looping through the cohesin loading factor NIPBL, and drives transcriptional elongation. Simultaneously, JMJD3 induces Ink4a and degrades PHF20 (via Trim26) in a KLF4-independent manner.\",\n      \"method\": \"ChIP-seq for H3K27me3 and JMJD3 during reprogramming, Co-IP of JMJD3-KLF4 and JMJD3-NIPBL, enhancer-promoter looping analysis, Trim26-mediated PHF20 degradation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP-seq, Co-IP, looping, degradation assays) establishing multiple mechanistic arms\",\n      \"pmids\": [\"33033262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STAT3 binds the Jmjd3 promoter and represses Jmjd3 transcription in glioblastoma stem cells. STAT3 inhibition upregulates JMJD3, which demethylates H3K27 at differentiation gene promoters (Myt1, FGF21, GDF15), slows glioblastoma stem cell growth, and Jmjd3 knockdown rescues STAT3 inhibitor-induced neurosphere formation defects.\",\n      \"method\": \"STAT3 ChIP at Jmjd3 promoter, JMJD3 overexpression/knockdown, H3K27 demethylation ChIP at differentiation gene promoters, neurosphere assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — STAT3 ChIP, H3K27 ChIP, genetic rescue, single lab\",\n      \"pmids\": [\"28384648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In reptilian temperature-dependent sex determination, STAT3 phosphorylated at the female-producing temperature binds the Kdm6b locus and represses Kdm6b transcription, blocking the male developmental pathway. Ca2+ influx elevated at female temperature mediates STAT3 phosphorylation as a temperature-sensitive regulator.\",\n      \"method\": \"ChIP for pSTAT3 at Kdm6b locus, Ca2+ manipulation, STAT3 phosphorylation assays in turtle embryos at different temperatures\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct pSTAT3 binding at Kdm6b locus with causal Ca2+/STAT3 signaling established, single study\",\n      \"pmids\": [\"32299951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JMJD3 (but not UTX) removes H3K27me3 marks at the Has2 locus in muscle stem cells to initiate hyaluronic acid (HA) production. This JMJD3-driven HA synthesis establishes an extracellular matrix enabling MuSCs to exit quiescence and overcome inhibitory inflammation during muscle regeneration.\",\n      \"method\": \"JMJD3/UTX-specific knockdown in MuSCs, ChIP for H3K27me3 at Has2 locus, HA production assays, in vitro and in vivo muscle regeneration models\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — paralog-specific comparison (JMJD3 vs UTX), ChIP at target locus, functional HA assay, in vivo validation\",\n      \"pmids\": [\"35926054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6B promotes CDK4/6-pRB-E2F oncogenic pathway in MYCN-amplified neuroblastoma via H3K27me3-dependent enhancer-promoter interactions: KDM6B inhibition reduces H3K27me3 but also decreases the enhancer mark H3K4me1 at CTCF/BORIS binding sites, disrupting long-range chromatin interactions of MYCN and E2F targets.\",\n      \"method\": \"KDM6B inhibition with GSK-J4, ATAC-seq for chromatin accessibility, H3K27me3/H3K4me1 ChIP, CDK4/6 overexpression and Rb1 KO resistance experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal chromatin assays (ATAC-seq, H3K27me3 ChIP, H3K4me1 ChIP), genetic rescue experiments, mechanistic pathway placement\",\n      \"pmids\": [\"34893606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6B mediates H3K27me3 demethylation at the LDHA promoter to upregulate LDHA expression in osteosarcoma cells, promoting aerobic glycolysis and lung metastasis. ChIP-seq and RNA-seq identified LDHA as a direct KDM6B target.\",\n      \"method\": \"ChIP-seq, RNA-seq, ChIP-qPCR for H3K27me3 at LDHA promoter, KDM6B knockdown with LDHA rescue, in vivo metastasis model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq, RNA-seq, and in vivo rescue experiment, single lab\",\n      \"pmids\": [\"33664867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In macrophages, interferon-β regulates Jmjd3 expression via the JAK/STAT pathway, and JMJD3 induces NF-κB-mediated inflammatory gene transcription by removing repressive H3K27me3 marks from inflammatory gene promoters. Myeloid-specific Jmjd3 deletion preserved H3K27me3 at inflammatory gene promoters and reduced AAA expansion.\",\n      \"method\": \"Myeloid-specific Jmjd3 KO mice (Jmjd3f/fLyz2Cre+), single-cell RNA-seq of human AAA tissue, H3K27me3 ChIP at inflammatory gene promoters, pharmacological inhibition in elastase/angiotensin II AAA models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — myeloid-specific genetic KO with ChIP validation, single-cell transcriptomics, and in vivo disease model, multiple methods\",\n      \"pmids\": [\"33779682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6B demethylates H3K27me3 at the cyclin D1 promoter and cooperates with Smad2/3 to promote cyclin D1 transcription in prostate cancer. Androgen receptor decreases KDM6B transcription, placing KDM6B downstream of androgen signaling.\",\n      \"method\": \"ChIP for H3K27me3 at cyclin D1 promoter, KDM6B overexpression/knockdown, Co-IP of KDM6B and Smad2/3, AR-KDM6B transcriptional regulation assay, in vivo xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, in vivo model, single lab\",\n      \"pmids\": [\"33414463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6B is recruited to the KDM6B locus by the SMAD2/3 complex downstream of activin A signaling in hippocampal neurons. Activin A treatment induces KDM6B expression via SMAD2/3 binding at the Kdm6b gene, conserved in human forebrain neurons.\",\n      \"method\": \"ChIP experiments with hippocampal lysates for SMAD2/3 binding at Kdm6b gene after electroconvulsive seizures, human ESC-derived forebrain neuron validation\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP in vivo and human cell validation, single lab\",\n      \"pmids\": [\"26215835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6B-dependent H3K27me3 demethylation is required for early CD8+ T cell differentiation: KDM6B is rapidly upregulated prior to the first cell division after naive T cell activation, enabling H3K27me3 removal at differentiation/proliferation genes. KDM6B inhibition limits the magnitude of primary virus-specific CD8+ T cell responses and memory formation.\",\n      \"method\": \"Genome-wide ATAC-seq, H3K27me3 ChIP-seq, RNA-seq, KDM6B inhibition during virus-specific T cell responses in vivo\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide chromatin accessibility, H3K27me3 ChIP-seq, and in vivo functional immune assays with multiple orthogonal methods\",\n      \"pmids\": [\"33730567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM6B interacts with transcription factor TFDP1 to activate Trp53 expression during palatogenesis. Without KDM6B, TFDP1 cannot activate Trp53. Activity of H3K27me3 at the Trp53 promoter is antagonistically controlled by KDM6B and EZH2. KDM6A cannot compensate for KDM6B loss in this context.\",\n      \"method\": \"Conditional Kdm6b KO in cranial neural crest cells, ChIP for H3K27me3 at Trp53 promoter, Co-IP/interaction assays of KDM6B and TFDP1, rescue experiments with Kdm6a\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, ChIP, protein interaction, paralog rescue experiment, single lab\",\n      \"pmids\": [\"35212626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM6B cooperates with Tau to regulate synaptic plasticity and cognition. Tau interacts with KDM6B and recruits it to the promoters of Slc17a7 (VGLUT1) and Slc17a6 (VGLUT2) in neurons, reducing local H3K27me3 and inducing VGLUT1/2 expression. Conditional KDM6B KO in excitatory neurons reduces spine density and impairs memory.\",\n      \"method\": \"Conditional KO in excitatory neurons, ChIP for H3K27me3 at VGLUT1/2 promoters, Co-IP of KDM6B and Tau, spine density/synaptic activity measurements, Tau KO loss-of-function rescue\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, conditional KO with behavioral and synaptic phenotypes, single lab\",\n      \"pmids\": [\"36028572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM6B promotes PARthanatos (PARP-1-dependent cell death) in response to alkylating agents by suppressing MGMT expression: KDM6B knockout reduces H3K27me3 at the MGMT promoter, enhancing MGMT expression and direct DNA repair, thereby inhibiting PARP-1 hyperactivation. KDM6B KO also triggers sustained Chk1 phosphorylation activating a secondary XRCC1-dependent repair pathway.\",\n      \"method\": \"KDM6B KO, ChIP for H3K27me3 at MGMT promoter, PARP-1 hyperactivation assays, MGMT expression and DNA repair functional assays, Chk1 phosphorylation analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with ChIP, functional DNA repair assays, checkpoint signaling, single lab\",\n      \"pmids\": [\"35648484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Kdm6b regulates motor neuron subtype diversification by working together with the transcription factor complex Isl1-Lhx3. Kdm6b promotes MMC and HMC fates while inhibiting LMC and PGC identities in mouse embryonic spinal cord. Single-cell RNA-seq demonstrated cell-type heterogeneity dependent on Kdm6b.\",\n      \"method\": \"Conditional Kdm6b KO in mouse embryonic motor neurons, single-cell RNA-seq, Isl1-Lhx3 complex interaction studies, motor column fate analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with scRNA-seq and transcription factor complex studies, single lab\",\n      \"pmids\": [\"35177643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In the context of diabetic wound healing, IL-6 activates the JAK1,3/STAT3 pathway to regulate JMJD3 expression in diabetic wound macrophages. Late-elevated JMJD3 induces NFκB-mediated inflammatory transcription via H3K27me3 removal. JMJD3 also controls STING (Tmem173) gene expression in wound macrophages through an H3K27me3 mechanism.\",\n      \"method\": \"Myeloid-specific Jmjd3 KO mice, single-cell RNA-seq, RNA-seq of isolated wound macrophages, H3K27me3 ChIP, nanoparticle-mediated JMJD3 inhibition in diabetic wounds\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — myeloid-specific KO, scRNA-seq, H3K27me3 ChIP, in vivo therapeutic intervention, single lab\",\n      \"pmids\": [\"36127466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFNβ reduces the cellular α-ketoglutarate/succinate ratio by inhibiting isocitrate dehydrogenase and boosting succinate, which potently blocks the JMJD3-IRF4-dependent M2 macrophage polarization pathway. Supplementation with α-ketoglutarate reverses IFNβ-mediated suppression of JMJD3-IRF4 responses.\",\n      \"method\": \"Metabolic flux analysis (isotope tracing), α-ketoglutarate supplementation rescue, macrophage polarization assays, JMJD3-IRF4 pathway functional studies\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolic mechanism with rescue experiment, multiple cell-based assays, single lab\",\n      \"pmids\": [\"35443173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Myeloid-specific Kdm6b deletion enhances antigen presentation, interferon response, and phagocytosis in myeloid cells by inhibiting mediators of immune suppression including Mafb, Socs3, and Sirpa. This reprogramming sensitizes glioblastoma to anti-PD1 immunotherapy. Pharmacological KDM6B inhibition mirrors the genetic Kdm6b deletion phenotype.\",\n      \"method\": \"Myeloid-specific Kdm6b KO mice with GBM tumor model, single-cell and spatial transcriptomics, mechanistic gene expression studies, anti-PD1 combination treatment in vivo\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — myeloid-specific genetic KO with comprehensive transcriptomics, pharmacological validation, in vivo immune checkpoint data, multiple methods\",\n      \"pmids\": [\"37653141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The lncRNA DNM3OS physically interacts with KDM6B in the nucleus of HCC cells. This DNM3OS-KDM6B association reduces H3K27me3 at the TIAM1 promoter, inducing TIAM1 expression and promoting HCC metastasis.\",\n      \"method\": \"Nuclear localization and pulldown of DNM3OS-KDM6B interaction, ChIP for H3K27me3 at TIAM1 promoter, TIAM1 rescue experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/pulldown with ChIP, single lab, lncRNA-protein interaction\",\n      \"pmids\": [\"33472090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM6B functions as a coactivator of HIF-1α-mediated Nox4 transactivation in response to intermittent hypoxia (IH). KDM6B protein and enzyme activity are increased by IH independently of HIF-1α. KDM6B blockade abolishes HIF-1α binding to the Nox4 HRE promoter and prevents IH-induced hypertension in vivo.\",\n      \"method\": \"ChIP for HIF-1α binding at Nox4 HRE, KDM6B shRNA and pharmacological inhibition (GSKJ4), KDM6B enzyme activity assay, rat IH hypertension model\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, enzyme activity assay, shRNA KD, in vivo rat model, single lab\",\n      \"pmids\": [\"34297635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Conditional deletion of Kdm6b (using Col2a1-CreER) in chondrocytes causes skeletal abnormalities and accelerated osteoarthritis via inhibition of chondrocyte anabolic gene expression. RNA-seq identified downregulation of anabolic chondrocyte genes in Kdm6b-deficient chondrocytes.\",\n      \"method\": \"Conditional Kdm6b KO in cartilage (Col2a1-CreER), RNA-seq, intra-articular shRNA lentiviral injection, OA histological scoring\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional genetic KO with RNA-seq, in vivo disease model, single lab\",\n      \"pmids\": [\"28314754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM6B (JMJD3) expression is induced by the EBV oncogene LMP1 in germinal centre B cells. KDM6B depletion restores H3K27me3 trimethylation on KDM6B target genes in Hodgkin's lymphoma cells.\",\n      \"method\": \"LMP1 ectopic expression, KDM6B depletion, ChIP for H3K27me3 at KDM6B target gene loci\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP with genetic manipulation demonstrating LMP1→KDM6B→H3K27me3 axis, single lab\",\n      \"pmids\": [\"21242977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JMJD3 expression is induced by 1,25(OH)2D3 in a VDR-dependent manner (abolished by cycloheximide, requiring new protein synthesis). JMJD3 modulates vitamin D receptor target gene expression; knockdown of JMJD3 or expression of an inactive mutant JMJD3 reduces 1,25(OH)2D3-induced gene activation and epithelial phenotype, and upregulates EMT inducers.\",\n      \"method\": \"JMJD3 promoter activation assays, VDR-dependent expression analysis, JMJD3 knockdown and inactive mutant expression, ChIP for H3K27me3 at VDR target gene promoters\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — catalytic mutant and ChIP analysis in VDR-dependent context, single lab\",\n      \"pmids\": [\"21890490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM6B demethylates H3K27me3 at neuronal gene promoters to activate transcription during neuroblastoma differentiation. KDM6B expression is upregulated by retinoic acid via HOXC9. KDM6B physically interacts with HOXC9 to target neuronal genes for epigenetic activation, and is required for HOXC9-induced differentiation.\",\n      \"method\": \"ChIP for H3K27me3 at neuronal gene promoters, KDM6B overexpression/depletion, Co-IP of KDM6B and HOXC9, retinoic acid treatment\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, genetic manipulation with defined differentiation phenotype, single lab\",\n      \"pmids\": [\"30631055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-93-5p targets the 3' UTR of KDM6B to inhibit its protein translation. KDM6B binds the BMP2 promoter and demethylates H3K27me3 marks to activate BMP2 transcription in dental pulp stem cells, promoting odontogenic differentiation and tertiary dentin formation.\",\n      \"method\": \"Dual luciferase reporter assay for miR-93-5p/KDM6B 3'UTR, ChIP-qPCR for KDM6B binding and H3K27me3 at BMP2 promoter, KDM6B overexpression in rat pulpotomy model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter, ChIP-qPCR, in vivo model validation, single lab\",\n      \"pmids\": [\"38218880\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM6B (JMJD3) is an inducible histone H3K27me2/me3 demethylase that activates gene transcription by removing repressive polycomb marks at promoters, gene bodies, and enhancers; beyond its catalytic activity, it also operates through demethylase-independent mechanisms including recruitment of E3 ubiquitin ligase Trim26 to degrade PHF20, scaffolding enhancer-promoter looping via NIPBL, and coactivation of transcription factors such as NF-κB, C/EBPβ, ISL1, KLF4, KLF2, and HOXC9 in a context-dependent manner across development, immunity, metabolism, and disease.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM6B (JMJD3) is an inducible histone H3K27me2/me3 demethylase that activates gene transcription by removing repressive polycomb marks at promoters, gene bodies, and enhancers, thereby licensing context-dependent transcriptional programs across development, immunity, metabolism, and disease [#0, #3]. Its catalytic core converts H3K27me3 to lower methylation states, displacing polycomb proteins [#0], and at TGF-\\u03b2-responsive loci it acts not only at promoters but within gene bodies to facilitate elongating RNA Polymerase II progression [#3]. KDM6B is overwhelmingly deployed as a recruited cofactor: sequence-specific transcription factors and signaling effectors\\u2014including NF-\\u03baB [#8], C/EBP\\u03b2 [#15], ISL1 and the Isl1-Lhx3 complex [#9, #31], KLF2 [#16], KLF4 [#18], HOXC9 [#40], Smad2/3 [#25], TFDP1 [#28], and p53 [#6]\\u2014physically engage KDM6B and direct it to specific enhancers and promoters where it erases H3K27me3 to drive lineage commitment, T-cell trafficking and differentiation, myeloid and metabolic gene programs, and tumor-associated transcription. Beyond catalysis, KDM6B operates through demethylase-independent mechanisms: it recruits the E3 ligase Trim26 to ubiquitinate and degrade PHF20 [#1, #18], scaffolds enhancer-promoter looping via the cohesin loading factor NIPBL [#18], and activates MAPK-pathway genes (ELK1, FOS) and pro-differentiation AP-1/IER programs in a chromatin-modification-independent manner [#10, #17]. KDM6B expression is itself a regulatory hub, induced or repressed by signaling inputs including TGF-\\u03b2/activin-SMAD [#2, #26], interferon/JAK-STAT [#19, #20, #24], vitamin D/VDR [#39], and microRNA targeting [#41], positioning it as a signal-responsive switch that couples extracellular cues to polycomb-controlled gene activation.\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the founding biochemical identity of KDM6B, answering whether it is an enzyme acting on chromatin and showing it actively reverses a repressive polycomb mark.\",\n      \"evidence\": \"In vitro demethylase assay, ectopic expression with H3K27me3 immunostaining, and C. elegans ortholog genetics\",\n      \"pmids\": [\"17713478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which transcription factors target the enzyme to specific loci\", \"No structural basis for substrate selectivity\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected KDM6B to upstream signaling and oncogenic induction, showing its expression is driven by VDR and the EBV oncogene LMP1 to control polycomb status at target genes.\",\n      \"evidence\": \"VDR-dependent induction with catalytic mutant and ChIP; LMP1 ectopic expression with H3K27me3 ChIP in lymphoma cells\",\n      \"pmids\": [\"21890490\", \"21242977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map the full target gene set\", \"Mechanism of locus-specific recruitment not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the dual transcriptional logic of KDM6B in TGF-\\u03b2 responses\\u2014activating SNAI1 to drive EMT and acting within gene bodies to enable RNAPII elongation, not just initiation.\",\n      \"evidence\": \"Knockdown/overexpression with promoter ChIP and invasion assays; genome-wide ChIP-seq for JMJD3, elongating RNAPII, and H3K27me3\",\n      \"pmids\": [\"23152497\", \"23243002\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How JMJD3 couples to elongation machinery mechanistically not defined\", \"EMT findings from a single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that KDM6B acts both catalytically and non-catalytically, including a demethylase-independent arm recruiting Trim26 to degrade PHF20, and showed it balances PRC2 to set lineage fates.\",\n      \"evidence\": \"iPSC reprogramming in Jmjd3-deficient MEFs with Co-IP, ubiquitination assays, catalytic mutants; embryo genetic manipulation with H3K27me3 ChIP at lineage loci; ESC mesoderm differentiation assays\",\n      \"pmids\": [\"23452852\", \"23671187\", \"23856522\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KDM6B selects PHF20 versus other substrates for Trim26 unclear\", \"Stoichiometry of KDM6B vs PRC2 in fate decisions not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Generalized KDM6B as a recruited transcription-factor cofactor by showing direct physical partnerships with NF-\\u03baB, ISL1, and p53 that target it to specific enhancers and promoters.\",\n      \"evidence\": \"Co-IP and ChIP/ChIP-seq with functional inactivation in keratinocyte wound healing, cardiac progenitors, and DNA-damage responses\",\n      \"pmids\": [\"26802933\", \"27105846\", \"24797517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these interactions are direct or bridged is not always resolved\", \"Domain requirements for each partnership incompletely mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated catalysis-independent transcriptional activation as a bona fide mechanism, showing catalytically dead KDM6B still activates MAPK genes, and extended KDM6B roles to chondrocyte anabolism.\",\n      \"evidence\": \"CRISPR KO, RNA-seq, ChIP-qPCR and catalytically inactive mutant overexpression in myeloma; conditional cartilage KO with RNA-seq and OA models\",\n      \"pmids\": [\"28487543\", \"28314754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The chromatin-independent effector mechanism on MAPK loci not defined\", \"How KDM6B activates genes without modifying H3K27 is unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped KDM6B into metabolic and disease-specific transcriptional circuits, partnering with SIRT1/PPAR\\u03b1, IRF4, and C/EBP\\u03b2 in feedback loops controlling \\u03b2-oxidation, lymphoma survival, and myeloid differentiation.\",\n      \"evidence\": \"Co-IP, ChIP, liver-specific knockdown with metabolic phenotyping; demethylase-dependent rescue assays in DLBCL; Co-IP/RNA-seq/ChIP in AML\",\n      \"pmids\": [\"29911994\", \"27102442\", \"30135572\", \"29753027\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Gene-specificity determinants of SIRT1 partnership not defined\", \"Whether feedback loops generalize beyond the studied systems unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Integrated the multiple mechanistic arms of KDM6B during reprogramming, showing KLF4-directed enhancer demethylation, NIPBL-dependent enhancer-promoter looping, elongation, and parallel PHF20 degradation.\",\n      \"evidence\": \"ChIP-seq for JMJD3/H3K27me3, Co-IP of JMJD3-KLF4 and JMJD3-NIPBL, looping analysis, and Trim26-PHF20 degradation assays during reprogramming\",\n      \"pmids\": [\"33033262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NIPBL recruitment is mechanistically achieved by KDM6B is unresolved\", \"Relative contribution of each arm to reprogramming not partitioned\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded KDM6B into chromatin-architecture and stress-adaptive immune/metabolic programs, including paralog-specific (vs UTX) action at Has2, enhancer-looping in neuroblastoma, glycolytic LDHA control, and CD8+ T cell priming.\",\n      \"evidence\": \"Paralog-specific knockdown with ChIP and HA assays; ATAC-seq and H3K4me1/H3K27me3 ChIP with genetic rescue in neuroblastoma; ChIP-seq/RNA-seq in osteosarcoma; ATAC-seq/H3K27me3 ChIP-seq/RNA-seq in T cells\",\n      \"pmids\": [\"35926054\", \"34893606\", \"33664867\", \"33730567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of JMJD3 vs UTX functional specialization unknown\", \"How KDM6B influences H3K4me1 and CTCF/BORIS-dependent looping mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Consolidated KDM6B as a recruited partner across diverse tissues\\u2014TFDP1 in palatogenesis, Tau in neurons, Isl1-Lhx3 in motor neurons, and macrophage inflammatory programs\\u2014and linked it to DNA-repair-coupled cell death.\",\n      \"evidence\": \"Conditional KOs with ChIP, Co-IP, scRNA-seq, behavioral/synaptic readouts, and MGMT/PARP-1 DNA repair assays\",\n      \"pmids\": [\"35212626\", \"36028572\", \"35177643\", \"36127466\", \"35648484\", \"35443173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why paralog KDM6A cannot compensate in several contexts is unexplained\", \"Direct versus indirect nature of the Tau interaction not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established KDM6B as a therapeutic target in tumor immunity, showing myeloid-specific deletion reprograms suppressive myeloid cells and sensitizes glioblastoma to checkpoint blockade.\",\n      \"evidence\": \"Myeloid-specific Kdm6b KO with GBM models, single-cell and spatial transcriptomics, pharmacological inhibition, and anti-PD1 combination in vivo\",\n      \"pmids\": [\"37653141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct KDM6B targets driving Mafb/Socs3/Sirpa suppression not pinpointed\", \"Whether effects are demethylase-dependent not fully partitioned\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended upstream regulation of KDM6B to microRNA control, showing miR-93-5p represses KDM6B translation while KDM6B activates BMP2 to drive odontogenic differentiation.\",\n      \"evidence\": \"Dual luciferase reporter, ChIP-qPCR at BMP2 promoter, and in vivo pulpotomy model\",\n      \"pmids\": [\"38218880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Broader miRNA regulatory network for KDM6B not mapped\", \"Single-lab validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how KDM6B's catalytic and non-catalytic activities are selected and balanced at individual loci, and what structural features dictate its partner- and paralog-specific recruitment.\",\n      \"evidence\": \"No single study in the corpus resolves the determinants of catalytic versus scaffold function genome-wide\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model explaining partner-specific recruitment\", \"Determinants of demethylase-dependent vs -independent gene activation undefined\", \"Mechanism distinguishing KDM6B from KDM6A/UTX at shared loci unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 21]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [10, 16, 18]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 9, 25, 36, 40]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 35]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 3, 18]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 10, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [24, 27, 34]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 25]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 12, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [14, 22, 34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRIM26\", \"PHF20\", \"NIPBL\", \"KLF4\", \"ISL1\", \"NFKB1\", \"CEBPB\", \"SMAD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}