{"gene":"KDM3B","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2012,"finding":"KDM3B possesses histone H3K9-me1/2 demethylase activity (via its JmjC domain) and activates leukemogenic oncogene LMO2 expression through a synergistic interaction with the histone acetyltransferase CBP, forming a co-activator complex at the LMO2 locus.","method":"ChIP-chip genome-wide occupancy analysis, in vitro demethylase activity assays, co-immunoprecipitation, transcriptional reporter assays in HL-60 cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — enzymatic activity demonstrated in vitro, synergistic interaction with CBP shown by co-IP, functional transcriptional activation confirmed with multiple orthogonal methods in a single rigorous study","pmids":["22615488"],"is_preprint":false},{"year":2015,"finding":"Kdm3b demethylates H3K9me1/2 in vivo; knockout mice show elevated H3K9me1/2/3 in ovary and uterus, reduced circulating IGF-1 (via decreased renal IGFBP-3 expression), reduced 17β-estradiol, and defects in postnatal growth, ovulation, fertilization, and uterine decidual response.","method":"Kdm3b knockout mouse model, hormone measurements (RIA/ELISA), histology, ChIP, gene expression analysis","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean knockout with multiple orthogonal phenotypic and molecular readouts establishing pathway placement in IGF-1 and estradiol axes","pmids":["25892958"],"is_preprint":false},{"year":2015,"finding":"KDM3B represses ANGPT1 transcription independently of its JmjC-domain H3K9 demethylase catalytic activity, instead acting through physical interaction with the co-repressor SMRT at the ANGPT1 promoter.","method":"Co-immunoprecipitation, ChIP at ANGPT1 promoter, JmjC-domain mutant analysis, MTT and wound-healing assays","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — single lab, reciprocal interaction shown by co-IP and ChIP, but mechanistic follow-up is partial","pmids":["25413303"],"is_preprint":false},{"year":2015,"finding":"Kdm3b knockout male mice show reduced spermatogenesis (44% fewer mature sperm), decreased sperm motility, and markedly reduced circulating 17β-estradiol, without changes in testosterone or androgen receptor target genes, indicating Kdm3b-mediated H3K9 demethylation is required for spermatogenesis and male sexual behavior.","method":"Kdm3b knockout mouse model, sperm counts, motility assays, hormone measurements, gene expression analysis","journal":"International journal of biological sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean knockout with multiple quantitative phenotypic readouts, pathway placement defined by negative result on androgen axis and positive result on estradiol axis","pmids":["26681924"],"is_preprint":false},{"year":2017,"finding":"KDM3B binds retinoic acid response elements (RARE) in the HOXA1 locus (not the promoter directly) and regulates HOXA1 expression by modulating H3K9 monomethylation and dimethylation specifically at RARE; KDM3B knockdown increases H3K9me1 but decreases H3K9me2 at RARE.","method":"ChIP at RARE and HOXA1 promoter, KDM3B knockdown, real-time PCR, Western blot, microarray profiling","journal":"Leukemia & lymphoma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly mapping KDM3B occupancy to RARE, combined with gene expression changes upon knockdown in two orthogonal methods","pmids":["28540746"],"is_preprint":false},{"year":2018,"finding":"KDM3B knockout in HepG2 hepatocarcinoma cells retards cell cycle and proliferation, induces mitotic spindle multipolarity (~30% of cells), and downregulates cell-cycle genes including CDC123; additionally, Cyclin D1 protein is reduced post-translationally via proteasomal degradation without changes in CCND1 mRNA.","method":"CRISPR/Cas9 knockout, RNA-seq, flow cytometry, immunofluorescence for spindle multipolarity, Western blot, proteasome inhibitor assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockout with multiple orthogonal readouts (RNA-seq, flow cytometry, spindle imaging, Western blot) in a single study","pmids":["30514438"],"is_preprint":false},{"year":2019,"finding":"KDM3B knockdown in NB4 APL cells alters global distribution of H3K9me1/2, increases chromatin accessibility (ATAC-seq), promotes cell-cycle progression, and inhibits ATRA-induced degradation of the PML/RARα oncoprotein, indicating KDM3B maintains chromatin compaction to facilitate PML/RARα degradation.","method":"KDM3B knockdown, ChIP-seq, ATAC-seq, flow cytometry, Western blot for PML/RARα","journal":"Cancer cell international","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal omics approaches (ChIP-seq, ATAC-seq) combined with functional assays in a single study directly linking KDM3B activity to chromatin state and oncoprotein stability","pmids":["31592194"],"is_preprint":false},{"year":2019,"finding":"KDM3B enzymatic activity (H3K9 demethylase) is required for its role in supporting CRPC cell proliferation; genetic rescue of KDM3B knockout with catalytically inactive KDM3B failed to restore proliferation. KDM3B loss in CRPC cells downregulates metabolic enzymes ARG2 and RDH11 and causes decreases in critical amino acids.","method":"shRNA screen, CRISPR/Cas9 knockout, enzymatically-inactive KDM3B rescue experiment, transcriptome analysis, metabolomics","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — active-site mutagenesis/rescue experiment directly establishing requirement for catalytic activity, combined with transcriptome and metabolomics in a single focused study","pmids":["31822799"],"is_preprint":false},{"year":2020,"finding":"KDM3B overexpression protects against ferroptosis induced by Erastin (an SLC7A11 inhibitor) by upregulating SLC7A11 expression through cooperation with the transcription factor ATF4, and KDM3B overexpression decreases global H3K9 methylation in HT-1080 cells.","method":"KDM3B overexpression in HT-1080 cells, cell viability assays, Western blot, co-immunoprecipitation with ATF4, RT-PCR","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, co-IP with ATF4, functional viability assay and gene expression changes, but limited mechanistic depth on complex assembly","pmids":["32107878"],"is_preprint":false},{"year":2020,"finding":"JMJD1B (KDM3B) depletion increases protein levels of the histone chaperone tNASP, causing accumulation of newly synthesized histones H3 and H4 at early steps of the histone maturation cascade and perturbing chromatin assembly, establishing a role for KDM3B in histone supply and genome stability.","method":"JMJD1B knockdown, Western blot for tNASP and histones, chromatin assembly assay, fractionation","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean knockdown with specific molecular readout (tNASP accumulation, histone maturation defect), single lab with orthogonal fractionation and assembly assays","pmids":["32070414"],"is_preprint":false},{"year":2020,"finding":"KDM3B level increases in nutrient-deprived HCT116 cells and activates autophagy-related genes by demethylating H3K9me2 at their promoters; KDM3B depletion inhibits autophagic flux.","method":"KDM3B knockdown/overexpression, ChIP at autophagy gene promoters, H3K9me2 measurement, autophagic flux assay (LC3 puncta, Western blot)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly linking KDM3B occupancy and H3K9me2 reduction at autophagy gene promoters combined with functional autophagic flux assays","pmids":["32716961"],"is_preprint":false},{"year":2021,"finding":"KDM3A and KDM3B form a protein complex (demonstrated by IP-MS) that cooperates with core pluripotency transcription factors OCT4 and SOX2 to maintain H3K9me2/3 hypomethylation at pluripotency genes; co-depletion of KDM3A and KDM3B collapses the pluripotency gene regulatory network in porcine iPSCs.","method":"Immunoprecipitation–mass spectrometry (IP-MS), ChIP-seq, KDM3A/KDM3B co-depletion, genome-wide regulation analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS establishes complex, genome-wide ChIP-seq provides mechanistic context, single lab","pmids":["34042215"],"is_preprint":false},{"year":2021,"finding":"Heterozygous Kdm3b knockout mice show increased H3K9 dimethylation selectively in the granule cell layer of the cerebellum, impaired consolidation of cerebellum-dependent motor memory (optokinetic response learning), and altered expression of plasticity-related genes in the cerebellum.","method":"Heterozygous Kdm3b knockout mouse, optokinetic response behavioral assay, ChIP for H3K9me2, RNA-seq","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean haploinsufficiency model with behavioral, epigenomic, and transcriptomic readouts in a single study","pmids":["34217333"],"is_preprint":false},{"year":2022,"finding":"KDM3B downregulation (via siRNA) increases stability of F508del-CFTR protein and boosts functional rescue of the CFTR channel, suggesting KDM3B-mediated demethylation of CFTR lysine residues promotes CFTR ubiquitination and proteasomal degradation.","method":"siRNA library screen against human demethylases, CFTR stability assay, channel function assay (halide-sensitive YFP), Western blot","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA knockdown screen result, mechanism proposed (methylation/ubiquitination competition) but not directly confirmed by mutagenesis or structural data","pmids":["36077010"],"is_preprint":false},{"year":2024,"finding":"KDM3B selectively binds and is inhibited by small molecules P3FI-63 and P3FI-90; biophysical binding of P3FI-90 to KDM3B demonstrated by NMR and surface plasmon resonance (SPR); enzymatic assays confirm inhibition of KDM3B (highest selectivity among KDMs tested); combined knockdown of KDM3B and KDM1A phenocopies the inhibitor effects on PAX3-FOXO1 transcriptional activity and FP-RMS growth in vitro and in vivo.","method":"Enzymatic KDM inhibition assays, NMR, SPR biophysical binding, RNA-seq, ATAC-seq, genetic knockdown, in vitro and in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structural biophysical binding (NMR + SPR) plus enzymatic assay plus genetic rescue/knockdown with in vivo validation, multiple orthogonal methods in single rigorous study","pmids":["38402212"],"is_preprint":false},{"year":2024,"finding":"Loss of Kdm3b in IDH2- and TET2-mutant hematopoietic stem and progenitor cells (HSPCs) specifically reduces their fitness; Kdm3b loss leads to decreased expression of cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to JAK2 signaling inhibition.","method":"CRISPR/Cas9 screens in primary HSPCs ex vivo co-culture, gene expression analysis, genetic validation, JAK2 inhibitor treatment","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen with genetic validation and defined molecular mechanism (Mpl downregulation → JAK2 dependency), single lab","pmids":["38819218"],"is_preprint":false},{"year":2024,"finding":"Kdm3b loss in mouse retinal cone photoreceptors leads to accumulation of H3K9me1/2 at synapse assembly and vesicle transport genes (silencing them) and loss of H3K9me heterochromatin at apoptotic genes (activating them), resulting in cone photoreceptor apoptosis and altered cone ribbon synapse morphology.","method":"Kdm3b conditional knockout (retina), single-cell RNA-seq, ChIP-seq/CUT&TAG, ATAC-seq, immunofluorescence, histology","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockout with integrated transcriptomic and epigenomic analyses demonstrating direct mechanistic link between KDM3B loss, H3K9me redistribution, and target gene regulation","pmids":["39165843"],"is_preprint":false},{"year":2025,"finding":"KDM3B regulates postradiation fibrosis in prostate stroma by maintaining N6-methyladenosine (m6A) modification on LOX mRNA; reduced KDM3B expression (driven by rs17599026 SNP via circRNA/miRNA mechanisms) decreases m6A modification of LOX mRNA, increasing its stability and LOX protein expression, which promotes collagen cross-linking and fibrosis. α-ketoglutarate supplementation restores KDM3B protein levels, reduces LOX, and mitigates fibrosis.","method":"CRISPR-dead Cas9 prime editing to mimic SNP, RNA immunoprecipitation, transcript stability assay, Western blot, murine fibrosis model, α-KG supplementation","journal":"International journal of radiation oncology, biology, physics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA immunoprecipitation directly linking KDM3B to m6A modification of LOX mRNA, combined with in vivo murine validation and mechanistic rescue experiments, single lab","pmids":["40588066"],"is_preprint":false},{"year":2025,"finding":"KDM3B promotes neural invasion in colorectal cancer by demethylating H3K9me2 at the NTRK1 (TrkA) locus, increasing TrkA expression, which enables nerve growth factor (NGF) binding and downstream signaling to drive neural invasion.","method":"CUT&TAG, ATAC-seq, shKDM3B CRC cell line, in vivo and in vitro neural invasion assays, Western blot, clinical tissue TMT-proteomics","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CUT&TAG and ATAC-seq directly linking KDM3B to H3K9me2 reduction at NTRK1, with in vivo validation, single lab","pmids":["41488357"],"is_preprint":false},{"year":2025,"finding":"KDM3A and KDM3B interact with RNA processing factors EFTUD2 and PRMT5 (by proteomic analysis); acute degradation of KDM3A/KDM3B causes altered alternative splicing in mESCs independent of H3K9me2 status or catalytic activity, affecting splicing of chromatin/transcription factor genes including Dnmt3b and Tcf12.","method":"Proteomic analysis (co-IP/MS), auxin-inducible degron acute protein degradation, RNA-seq for splicing changes, H3K9me2 ChIP-seq, catalytic mutant comparison","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic co-IP plus acute degradation with orthogonal splicing and epigenomic readouts, catalytic independence established by comparison with H3K9me2 levels; single lab","pmids":["40510131"],"is_preprint":false},{"year":2025,"finding":"JMJD1B (KDM3B) acts as an arginine demethylase for FEN1 R192; JMJD1B-mediated demethylation of FEN1 R192 promotes FEN1 dissociation from PCNA and LIG1 recruitment during Okazaki fragment maturation; loss of JMJD1B causes unprocessed 5' flaps, induction of PARP1-dependent LIG3 recruitment, and DNA mutations (duplications).","method":"In vitro demethylation assay, PCNA binding assays, Jmjd1b knockout cells, FEN1 R192Q mutant analysis, DNA replication and mutagenesis assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic demethylation assay and mutagenesis of FEN1 R192 establish a novel non-histone substrate; preprint, not yet peer-reviewed","pmids":["41280084"],"is_preprint":true},{"year":2026,"finding":"KDM3B targets the SHP1 gene promoter by reducing H3K9me2 levels, thereby upregulating SHP1 expression; SHP1 suppresses STING signaling, so KDM3B inhibition attenuates SHP1-mediated STING inactivation, triggering type I interferon responses and CD8+ T cell recruitment in TNBC models.","method":"KDM3B knockout, ChIP for H3K9me2 at SHP1 promoter, Western blot, STING pathway analysis, in vivo tumor models with immune cell profiling, KDM3B inhibitor (P3FI-90) treatment","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly linking KDM3B to H3K9me2 reduction at SHP1 promoter combined with in vivo validation and pharmacological inhibitor, single lab","pmids":["42201640"],"is_preprint":false}],"current_model":"KDM3B is a JmjC domain-containing histone demethylase that removes mono- and di-methyl marks from H3K9 (H3K9me1/2), thereby activating target genes including LMO2, HOXA1, SLC7A11, NTRK1, and SHP1 through promoter/enhancer demethylation; it forms co-activator complexes with CBP and interacts with transcription factors (ATF4, OCT4/SOX2) and co-repressors (SMRT) in a context-dependent manner; its enzymatic activity is required for its proliferative and differentiation phenotypes in cancer cells; it also has non-canonical roles in histone maturation/supply, alternative splicing (via interaction with EFTUD2/PRMT5, independent of catalytic activity), regulation of LOX mRNA stability via m6A modification, and demethylation of the non-histone substrate FEN1 R192 to control Okazaki fragment maturation."},"narrative":{"mechanistic_narrative":"KDM3B is a JmjC-domain histone demethylase that removes mono- and di-methyl marks from histone H3 lysine 9 (H3K9me1/2), shaping chromatin compaction and accessibility to control transcriptional programs in development, hematopoiesis, and cancer [PMID:22615488, PMID:31592194, PMID:39165843]. By demethylating H3K9 at target loci, it activates context-specific genes — the leukemogenic oncogene LMO2 via a co-activator complex with the acetyltransferase CBP [PMID:22615488], retinoic-acid-responsive HOXA1 through RARE occupancy [PMID:28540746], autophagy genes under nutrient deprivation [PMID:32716961], the ferroptosis transporter SLC7A11 in cooperation with ATF4 [PMID:32107878], the neurotrophin receptor NTRK1/TrkA to drive neural invasion [PMID:41488357], and the phosphatase SHP1 which restrains STING-dependent type I interferon signaling [PMID:42201640]. Its catalytic activity is required for its proliferative role in castration-resistant prostate cancer, where loss downregulates metabolic enzymes ARG2 and RDH11 [PMID:31822799], and it functions within a KDM3A/KDM3B complex that sustains pluripotency-gene hypomethylation alongside OCT4 and SOX2 [PMID:34042215]. In vivo, Kdm3b loss elevates H3K9 methylation and produces defects in postnatal growth, ovulation, and the IGF-1/estradiol axes [PMID:25892958], spermatogenesis [PMID:26681924], cerebellar motor-memory consolidation [PMID:34217333], and cone photoreceptor survival through bidirectional H3K9me redistribution [PMID:39165843]. Beyond chromatin, KDM3B has catalysis-independent and non-histone roles: it represses ANGPT1 through the co-repressor SMRT [PMID:25413303], regulates alternative splicing via interaction with EFTUD2 and PRMT5 [PMID:40510131], maintains m6A modification of LOX mRNA to control fibrosis [PMID:40588066], limits accumulation of the histone chaperone tNASP during histone maturation [PMID:32070414], and demethylates arginine R192 of the flap endonuclease FEN1 to govern Okazaki-fragment maturation [PMID:41280084]. Selective small-molecule inhibitors (P3FI-63/P3FI-90) bind KDM3B and impair PAX3-FOXO1-driven rhabdomyosarcoma growth [PMID:38402212].","teleology":[{"year":2012,"claim":"Established KDM3B as a bona fide H3K9me1/2 demethylase and connected its enzymatic activity to oncogene activation, defining its molecular identity as a transcriptional co-activator.","evidence":"In vitro demethylase assays, ChIP-chip, and co-IP with CBP at the LMO2 locus in HL-60 cells","pmids":["22615488"],"confidence":"High","gaps":["Generality of the CBP co-activator complex beyond LMO2 not defined","Structural basis of substrate recognition not addressed"]},{"year":2015,"claim":"Knockout mice placed KDM3B-mediated H3K9 demethylation in the IGF-1 and estradiol hormonal axes, establishing in vivo physiological roles in growth, reproduction, and spermatogenesis.","evidence":"Kdm3b knockout mice with hormone measurements, histology, ChIP, and expression profiling","pmids":["25892958","26681924"],"confidence":"High","gaps":["Direct demethylase target genes in reproductive tissues incompletely mapped","Cell-autonomous vs systemic contributions not separated"]},{"year":2015,"claim":"Showed KDM3B can repress transcription independently of catalysis, revealing a non-enzymatic co-repressor mode of action.","evidence":"Co-IP and ChIP with SMRT at the ANGPT1 promoter plus JmjC-mutant analysis","pmids":["25413303"],"confidence":"Medium","gaps":["Single lab, partial mechanistic follow-up","Scope of SMRT-dependent repression beyond ANGPT1 unknown"]},{"year":2017,"claim":"Mapped KDM3B to a retinoic-acid response element rather than the promoter, demonstrating locus-specific tuning of H3K9 mono- versus di-methylation.","evidence":"ChIP at RARE and HOXA1 promoter with knockdown and expression profiling","pmids":["28540746"],"confidence":"Medium","gaps":["Opposite H3K9me1/me2 effects mechanistically unexplained","RARE-binding partner not identified"]},{"year":2018,"claim":"Linked KDM3B to cell-cycle progression and mitotic fidelity, showing loss causes spindle multipolarity and post-translational Cyclin D1 destabilization.","evidence":"CRISPR knockout in HepG2 with RNA-seq, flow cytometry, spindle imaging, and proteasome assays","pmids":["30514438"],"confidence":"Medium","gaps":["Mechanism linking KDM3B to Cyclin D1 degradation undefined","Direct vs indirect control of CDC123 not resolved"]},{"year":2019,"claim":"Demonstrated that KDM3B catalytic activity is required for cancer cell proliferation and that it maintains chromatin compaction influencing oncoprotein stability.","evidence":"Catalytically-inactive rescue in CRPC cells with metabolomics; ChIP-seq/ATAC-seq and PML/RARα assays in NB4 APL cells","pmids":["31822799","31592194"],"confidence":"High","gaps":["Direct demethylation targets driving metabolic gene loss not pinpointed","Connection between chromatin accessibility and oncoprotein degradation mechanistically indirect"]},{"year":2020,"claim":"Broadened KDM3B function across autophagy activation, ferroptosis protection, and non-catalytic histone-supply control, showing both demethylase-dependent and chaperone-regulatory roles.","evidence":"ChIP and autophagic flux assays (HCT116); ATF4 co-IP and viability assays (HT-1080); tNASP and histone maturation assays","pmids":["32716961","32107878","32070414"],"confidence":"Medium","gaps":["Mechanism of tNASP level control unknown","Whether ATF4 cooperation requires KDM3B catalysis not tested"]},{"year":2021,"claim":"Defined a KDM3A/KDM3B complex sustaining pluripotency networks and revealed haploinsufficient roles in cerebellar plasticity, establishing functional partnership with its paralog.","evidence":"IP-MS and ChIP-seq in porcine iPSCs; heterozygous knockout mice with behavioral and epigenomic readouts","pmids":["34042215","34217333"],"confidence":"Medium","gaps":["Stoichiometry and architecture of the KDM3A/KDM3B complex unresolved","Redundancy vs distinct functions of the two paralogs not separated"]},{"year":2022,"claim":"Implicated KDM3B in protein quality control by influencing F508del-CFTR stability, proposing a non-histone lysine demethylation–ubiquitination link.","evidence":"siRNA demethylase library screen with CFTR stability and channel function assays","pmids":["36077010"],"confidence":"Low","gaps":["Proposed CFTR lysine demethylation not confirmed by mutagenesis or structure","Single knockdown screen result"]},{"year":2024,"claim":"Delivered selective chemical probes and genetic evidence positioning KDM3B as a druggable dependency in fusion-driven rhabdomyosarcoma and mutant hematopoietic stem cells.","evidence":"NMR/SPR biophysical binding plus enzymatic and in vivo tumor assays for P3FI-90; CRISPR screens in IDH2/TET2-mutant HSPCs with JAK2 inhibition","pmids":["38402212","38819218"],"confidence":"High","gaps":["Co-dependency with KDM1A mechanistically unexplained","Whether HSPC fitness effect requires catalysis untested"]},{"year":2024,"claim":"Showed in vivo that KDM3B loss bidirectionally redistributes H3K9 methylation to both silence and activate distinct gene sets, driving photoreceptor apoptosis.","evidence":"Conditional retinal knockout with scRNA-seq, CUT&TAG/ChIP-seq, ATAC-seq, and histology","pmids":["39165843"],"confidence":"High","gaps":["Determinants of locus-specific gain vs loss of H3K9me unknown","Direct vs secondary effects on apoptotic genes not separated"]},{"year":2025,"claim":"Expanded KDM3B function into RNA biology and non-histone substrates: splicing regulation, m6A maintenance, immune evasion, and arginine demethylation of FEN1.","evidence":"Co-IP/MS with EFTUD2/PRMT5 and degron splicing analysis; RNA-IP linking KDM3B to LOX m6A; ChIP at SHP1 with STING/immune profiling; in vitro FEN1 R192 demethylation and PCNA-binding assays (preprint)","pmids":["40510131","40588066","42201640","41280084"],"confidence":"Medium","gaps":["Splicing role mechanism beyond EFTUD2/PRMT5 association unclear","FEN1 arginine demethylase activity awaits peer review and structural validation","How KDM3B influences m6A deposition on LOX mRNA mechanistically undefined"]},{"year":null,"claim":"How KDM3B selects between catalytic histone demethylation, non-catalytic co-regulation, RNA-associated roles, and non-histone substrate demethylation in a given cellular context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating substrate range","Rules governing locus- and context-specific recruitment unknown","Relative physiological importance of each activity not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,6,7,16,18,20,21]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,16]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,8,11]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[17,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,6,16]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,16]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,6,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,8,18,21]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[20]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[17,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[21]}],"complexes":["KDM3A/KDM3B complex"],"partners":["CBP","SMRT","ATF4","OCT4","SOX2","KDM3A","EFTUD2","PRMT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7LBC6","full_name":"Lysine-specific demethylase 3B","aliases":["JmjC domain-containing histone demethylation protein 2B","Jumonji domain-containing protein 1B","Nuclear protein 5qNCA","[histone H3]-dimethyl-L-lysine(9) demethylase 3B"],"length_aa":1761,"mass_kda":191.6,"function":"Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Demethylation of Lys residue generates formaldehyde and succinate. May have tumor suppressor activity","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q7LBC6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM3B","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2},{"gene":"CLNS1A","stoichiometry":0.2},{"gene":"NUCKS1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KDM3B","total_profiled":1310},"omim":[{"mim_id":"618846","title":"DIETS-JONGMANS SYNDROME; DIJOS","url":"https://www.omim.org/entry/618846"},{"mim_id":"617283","title":"YTH DOMAIN-CONTAINING PROTEIN 1; YTHDC1","url":"https://www.omim.org/entry/617283"},{"mim_id":"616504","title":"METHYLTRANSFERASE 14, N6-ADENOSINE-METHYLTRANSFERASE SUBUNIT; METTL14","url":"https://www.omim.org/entry/616504"},{"mim_id":"612472","title":"METHYLTRANSFERASE 3, N6-ADENOSINE-METHYLTRANSFERASE COMPLEX CATALYTIC SUBUNIT; METTL3","url":"https://www.omim.org/entry/612472"},{"mim_id":"609373","title":"LYSINE DEMETHYLASE 3B; KDM3B","url":"https://www.omim.org/entry/609373"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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demethylase activity assays, co-immunoprecipitation, transcriptional reporter assays in HL-60 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — enzymatic activity demonstrated in vitro, synergistic interaction with CBP shown by co-IP, functional transcriptional activation confirmed with multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"22615488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kdm3b demethylates H3K9me1/2 in vivo; knockout mice show elevated H3K9me1/2/3 in ovary and uterus, reduced circulating IGF-1 (via decreased renal IGFBP-3 expression), reduced 17β-estradiol, and defects in postnatal growth, ovulation, fertilization, and uterine decidual response.\",\n      \"method\": \"Kdm3b knockout mouse model, hormone measurements (RIA/ELISA), histology, ChIP, gene expression analysis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with multiple orthogonal phenotypic and molecular readouts establishing pathway placement in IGF-1 and estradiol axes\",\n      \"pmids\": [\"25892958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KDM3B represses ANGPT1 transcription independently of its JmjC-domain H3K9 demethylase catalytic activity, instead acting through physical interaction with the co-repressor SMRT at the ANGPT1 promoter.\",\n      \"method\": \"Co-immunoprecipitation, ChIP at ANGPT1 promoter, JmjC-domain mutant analysis, MTT and wound-healing assays\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — single lab, reciprocal interaction shown by co-IP and ChIP, but mechanistic follow-up is partial\",\n      \"pmids\": [\"25413303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Kdm3b knockout male mice show reduced spermatogenesis (44% fewer mature sperm), decreased sperm motility, and markedly reduced circulating 17β-estradiol, without changes in testosterone or androgen receptor target genes, indicating Kdm3b-mediated H3K9 demethylation is required for spermatogenesis and male sexual behavior.\",\n      \"method\": \"Kdm3b knockout mouse model, sperm counts, motility assays, hormone measurements, gene expression analysis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with multiple quantitative phenotypic readouts, pathway placement defined by negative result on androgen axis and positive result on estradiol axis\",\n      \"pmids\": [\"26681924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM3B binds retinoic acid response elements (RARE) in the HOXA1 locus (not the promoter directly) and regulates HOXA1 expression by modulating H3K9 monomethylation and dimethylation specifically at RARE; KDM3B knockdown increases H3K9me1 but decreases H3K9me2 at RARE.\",\n      \"method\": \"ChIP at RARE and HOXA1 promoter, KDM3B knockdown, real-time PCR, Western blot, microarray profiling\",\n      \"journal\": \"Leukemia & lymphoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly mapping KDM3B occupancy to RARE, combined with gene expression changes upon knockdown in two orthogonal methods\",\n      \"pmids\": [\"28540746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM3B knockout in HepG2 hepatocarcinoma cells retards cell cycle and proliferation, induces mitotic spindle multipolarity (~30% of cells), and downregulates cell-cycle genes including CDC123; additionally, Cyclin D1 protein is reduced post-translationally via proteasomal degradation without changes in CCND1 mRNA.\",\n      \"method\": \"CRISPR/Cas9 knockout, RNA-seq, flow cytometry, immunofluorescence for spindle multipolarity, Western blot, proteasome inhibitor assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockout with multiple orthogonal readouts (RNA-seq, flow cytometry, spindle imaging, Western blot) in a single study\",\n      \"pmids\": [\"30514438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM3B knockdown in NB4 APL cells alters global distribution of H3K9me1/2, increases chromatin accessibility (ATAC-seq), promotes cell-cycle progression, and inhibits ATRA-induced degradation of the PML/RARα oncoprotein, indicating KDM3B maintains chromatin compaction to facilitate PML/RARα degradation.\",\n      \"method\": \"KDM3B knockdown, ChIP-seq, ATAC-seq, flow cytometry, Western blot for PML/RARα\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal omics approaches (ChIP-seq, ATAC-seq) combined with functional assays in a single study directly linking KDM3B activity to chromatin state and oncoprotein stability\",\n      \"pmids\": [\"31592194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM3B enzymatic activity (H3K9 demethylase) is required for its role in supporting CRPC cell proliferation; genetic rescue of KDM3B knockout with catalytically inactive KDM3B failed to restore proliferation. KDM3B loss in CRPC cells downregulates metabolic enzymes ARG2 and RDH11 and causes decreases in critical amino acids.\",\n      \"method\": \"shRNA screen, CRISPR/Cas9 knockout, enzymatically-inactive KDM3B rescue experiment, transcriptome analysis, metabolomics\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — active-site mutagenesis/rescue experiment directly establishing requirement for catalytic activity, combined with transcriptome and metabolomics in a single focused study\",\n      \"pmids\": [\"31822799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM3B overexpression protects against ferroptosis induced by Erastin (an SLC7A11 inhibitor) by upregulating SLC7A11 expression through cooperation with the transcription factor ATF4, and KDM3B overexpression decreases global H3K9 methylation in HT-1080 cells.\",\n      \"method\": \"KDM3B overexpression in HT-1080 cells, cell viability assays, Western blot, co-immunoprecipitation with ATF4, RT-PCR\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, co-IP with ATF4, functional viability assay and gene expression changes, but limited mechanistic depth on complex assembly\",\n      \"pmids\": [\"32107878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD1B (KDM3B) depletion increases protein levels of the histone chaperone tNASP, causing accumulation of newly synthesized histones H3 and H4 at early steps of the histone maturation cascade and perturbing chromatin assembly, establishing a role for KDM3B in histone supply and genome stability.\",\n      \"method\": \"JMJD1B knockdown, Western blot for tNASP and histones, chromatin assembly assay, fractionation\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean knockdown with specific molecular readout (tNASP accumulation, histone maturation defect), single lab with orthogonal fractionation and assembly assays\",\n      \"pmids\": [\"32070414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM3B level increases in nutrient-deprived HCT116 cells and activates autophagy-related genes by demethylating H3K9me2 at their promoters; KDM3B depletion inhibits autophagic flux.\",\n      \"method\": \"KDM3B knockdown/overexpression, ChIP at autophagy gene promoters, H3K9me2 measurement, autophagic flux assay (LC3 puncta, Western blot)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly linking KDM3B occupancy and H3K9me2 reduction at autophagy gene promoters combined with functional autophagic flux assays\",\n      \"pmids\": [\"32716961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM3A and KDM3B form a protein complex (demonstrated by IP-MS) that cooperates with core pluripotency transcription factors OCT4 and SOX2 to maintain H3K9me2/3 hypomethylation at pluripotency genes; co-depletion of KDM3A and KDM3B collapses the pluripotency gene regulatory network in porcine iPSCs.\",\n      \"method\": \"Immunoprecipitation–mass spectrometry (IP-MS), ChIP-seq, KDM3A/KDM3B co-depletion, genome-wide regulation analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS establishes complex, genome-wide ChIP-seq provides mechanistic context, single lab\",\n      \"pmids\": [\"34042215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Heterozygous Kdm3b knockout mice show increased H3K9 dimethylation selectively in the granule cell layer of the cerebellum, impaired consolidation of cerebellum-dependent motor memory (optokinetic response learning), and altered expression of plasticity-related genes in the cerebellum.\",\n      \"method\": \"Heterozygous Kdm3b knockout mouse, optokinetic response behavioral assay, ChIP for H3K9me2, RNA-seq\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean haploinsufficiency model with behavioral, epigenomic, and transcriptomic readouts in a single study\",\n      \"pmids\": [\"34217333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM3B downregulation (via siRNA) increases stability of F508del-CFTR protein and boosts functional rescue of the CFTR channel, suggesting KDM3B-mediated demethylation of CFTR lysine residues promotes CFTR ubiquitination and proteasomal degradation.\",\n      \"method\": \"siRNA library screen against human demethylases, CFTR stability assay, channel function assay (halide-sensitive YFP), Western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single siRNA knockdown screen result, mechanism proposed (methylation/ubiquitination competition) but not directly confirmed by mutagenesis or structural data\",\n      \"pmids\": [\"36077010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM3B selectively binds and is inhibited by small molecules P3FI-63 and P3FI-90; biophysical binding of P3FI-90 to KDM3B demonstrated by NMR and surface plasmon resonance (SPR); enzymatic assays confirm inhibition of KDM3B (highest selectivity among KDMs tested); combined knockdown of KDM3B and KDM1A phenocopies the inhibitor effects on PAX3-FOXO1 transcriptional activity and FP-RMS growth in vitro and in vivo.\",\n      \"method\": \"Enzymatic KDM inhibition assays, NMR, SPR biophysical binding, RNA-seq, ATAC-seq, genetic knockdown, in vitro and in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structural biophysical binding (NMR + SPR) plus enzymatic assay plus genetic rescue/knockdown with in vivo validation, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"38402212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of Kdm3b in IDH2- and TET2-mutant hematopoietic stem and progenitor cells (HSPCs) specifically reduces their fitness; Kdm3b loss leads to decreased expression of cytokine receptors including Mpl, rendering mutant HSPCs preferentially susceptible to JAK2 signaling inhibition.\",\n      \"method\": \"CRISPR/Cas9 screens in primary HSPCs ex vivo co-culture, gene expression analysis, genetic validation, JAK2 inhibitor treatment\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen with genetic validation and defined molecular mechanism (Mpl downregulation → JAK2 dependency), single lab\",\n      \"pmids\": [\"38819218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Kdm3b loss in mouse retinal cone photoreceptors leads to accumulation of H3K9me1/2 at synapse assembly and vesicle transport genes (silencing them) and loss of H3K9me heterochromatin at apoptotic genes (activating them), resulting in cone photoreceptor apoptosis and altered cone ribbon synapse morphology.\",\n      \"method\": \"Kdm3b conditional knockout (retina), single-cell RNA-seq, ChIP-seq/CUT&TAG, ATAC-seq, immunofluorescence, histology\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with integrated transcriptomic and epigenomic analyses demonstrating direct mechanistic link between KDM3B loss, H3K9me redistribution, and target gene regulation\",\n      \"pmids\": [\"39165843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM3B regulates postradiation fibrosis in prostate stroma by maintaining N6-methyladenosine (m6A) modification on LOX mRNA; reduced KDM3B expression (driven by rs17599026 SNP via circRNA/miRNA mechanisms) decreases m6A modification of LOX mRNA, increasing its stability and LOX protein expression, which promotes collagen cross-linking and fibrosis. α-ketoglutarate supplementation restores KDM3B protein levels, reduces LOX, and mitigates fibrosis.\",\n      \"method\": \"CRISPR-dead Cas9 prime editing to mimic SNP, RNA immunoprecipitation, transcript stability assay, Western blot, murine fibrosis model, α-KG supplementation\",\n      \"journal\": \"International journal of radiation oncology, biology, physics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA immunoprecipitation directly linking KDM3B to m6A modification of LOX mRNA, combined with in vivo murine validation and mechanistic rescue experiments, single lab\",\n      \"pmids\": [\"40588066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM3B promotes neural invasion in colorectal cancer by demethylating H3K9me2 at the NTRK1 (TrkA) locus, increasing TrkA expression, which enables nerve growth factor (NGF) binding and downstream signaling to drive neural invasion.\",\n      \"method\": \"CUT&TAG, ATAC-seq, shKDM3B CRC cell line, in vivo and in vitro neural invasion assays, Western blot, clinical tissue TMT-proteomics\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CUT&TAG and ATAC-seq directly linking KDM3B to H3K9me2 reduction at NTRK1, with in vivo validation, single lab\",\n      \"pmids\": [\"41488357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM3A and KDM3B interact with RNA processing factors EFTUD2 and PRMT5 (by proteomic analysis); acute degradation of KDM3A/KDM3B causes altered alternative splicing in mESCs independent of H3K9me2 status or catalytic activity, affecting splicing of chromatin/transcription factor genes including Dnmt3b and Tcf12.\",\n      \"method\": \"Proteomic analysis (co-IP/MS), auxin-inducible degron acute protein degradation, RNA-seq for splicing changes, H3K9me2 ChIP-seq, catalytic mutant comparison\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic co-IP plus acute degradation with orthogonal splicing and epigenomic readouts, catalytic independence established by comparison with H3K9me2 levels; single lab\",\n      \"pmids\": [\"40510131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JMJD1B (KDM3B) acts as an arginine demethylase for FEN1 R192; JMJD1B-mediated demethylation of FEN1 R192 promotes FEN1 dissociation from PCNA and LIG1 recruitment during Okazaki fragment maturation; loss of JMJD1B causes unprocessed 5' flaps, induction of PARP1-dependent LIG3 recruitment, and DNA mutations (duplications).\",\n      \"method\": \"In vitro demethylation assay, PCNA binding assays, Jmjd1b knockout cells, FEN1 R192Q mutant analysis, DNA replication and mutagenesis assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic demethylation assay and mutagenesis of FEN1 R192 establish a novel non-histone substrate; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41280084\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KDM3B targets the SHP1 gene promoter by reducing H3K9me2 levels, thereby upregulating SHP1 expression; SHP1 suppresses STING signaling, so KDM3B inhibition attenuates SHP1-mediated STING inactivation, triggering type I interferon responses and CD8+ T cell recruitment in TNBC models.\",\n      \"method\": \"KDM3B knockout, ChIP for H3K9me2 at SHP1 promoter, Western blot, STING pathway analysis, in vivo tumor models with immune cell profiling, KDM3B inhibitor (P3FI-90) treatment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly linking KDM3B to H3K9me2 reduction at SHP1 promoter combined with in vivo validation and pharmacological inhibitor, single lab\",\n      \"pmids\": [\"42201640\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM3B is a JmjC domain-containing histone demethylase that removes mono- and di-methyl marks from H3K9 (H3K9me1/2), thereby activating target genes including LMO2, HOXA1, SLC7A11, NTRK1, and SHP1 through promoter/enhancer demethylation; it forms co-activator complexes with CBP and interacts with transcription factors (ATF4, OCT4/SOX2) and co-repressors (SMRT) in a context-dependent manner; its enzymatic activity is required for its proliferative and differentiation phenotypes in cancer cells; it also has non-canonical roles in histone maturation/supply, alternative splicing (via interaction with EFTUD2/PRMT5, independent of catalytic activity), regulation of LOX mRNA stability via m6A modification, and demethylation of the non-histone substrate FEN1 R192 to control Okazaki fragment maturation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM3B is a JmjC-domain histone demethylase that removes mono- and di-methyl marks from histone H3 lysine 9 (H3K9me1/2), shaping chromatin compaction and accessibility to control transcriptional programs in development, hematopoiesis, and cancer [#0, #6, #16]. By demethylating H3K9 at target loci, it activates context-specific genes — the leukemogenic oncogene LMO2 via a co-activator complex with the acetyltransferase CBP [#0], retinoic-acid-responsive HOXA1 through RARE occupancy [#4], autophagy genes under nutrient deprivation [#10], the ferroptosis transporter SLC7A11 in cooperation with ATF4 [#8], the neurotrophin receptor NTRK1/TrkA to drive neural invasion [#18], and the phosphatase SHP1 which restrains STING-dependent type I interferon signaling [#21]. Its catalytic activity is required for its proliferative role in castration-resistant prostate cancer, where loss downregulates metabolic enzymes ARG2 and RDH11 [#7], and it functions within a KDM3A/KDM3B complex that sustains pluripotency-gene hypomethylation alongside OCT4 and SOX2 [#11]. In vivo, Kdm3b loss elevates H3K9 methylation and produces defects in postnatal growth, ovulation, and the IGF-1/estradiol axes [#1], spermatogenesis [#3], cerebellar motor-memory consolidation [#12], and cone photoreceptor survival through bidirectional H3K9me redistribution [#16]. Beyond chromatin, KDM3B has catalysis-independent and non-histone roles: it represses ANGPT1 through the co-repressor SMRT [#2], regulates alternative splicing via interaction with EFTUD2 and PRMT5 [#19], maintains m6A modification of LOX mRNA to control fibrosis [#17], limits accumulation of the histone chaperone tNASP during histone maturation [#9], and demethylates arginine R192 of the flap endonuclease FEN1 to govern Okazaki-fragment maturation [#20]. Selective small-molecule inhibitors (P3FI-63/P3FI-90) bind KDM3B and impair PAX3-FOXO1-driven rhabdomyosarcoma growth [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established KDM3B as a bona fide H3K9me1/2 demethylase and connected its enzymatic activity to oncogene activation, defining its molecular identity as a transcriptional co-activator.\",\n      \"evidence\": \"In vitro demethylase assays, ChIP-chip, and co-IP with CBP at the LMO2 locus in HL-60 cells\",\n      \"pmids\": [\"22615488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the CBP co-activator complex beyond LMO2 not defined\", \"Structural basis of substrate recognition not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Knockout mice placed KDM3B-mediated H3K9 demethylation in the IGF-1 and estradiol hormonal axes, establishing in vivo physiological roles in growth, reproduction, and spermatogenesis.\",\n      \"evidence\": \"Kdm3b knockout mice with hormone measurements, histology, ChIP, and expression profiling\",\n      \"pmids\": [\"25892958\", \"26681924\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demethylase target genes in reproductive tissues incompletely mapped\", \"Cell-autonomous vs systemic contributions not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed KDM3B can repress transcription independently of catalysis, revealing a non-enzymatic co-repressor mode of action.\",\n      \"evidence\": \"Co-IP and ChIP with SMRT at the ANGPT1 promoter plus JmjC-mutant analysis\",\n      \"pmids\": [\"25413303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, partial mechanistic follow-up\", \"Scope of SMRT-dependent repression beyond ANGPT1 unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped KDM3B to a retinoic-acid response element rather than the promoter, demonstrating locus-specific tuning of H3K9 mono- versus di-methylation.\",\n      \"evidence\": \"ChIP at RARE and HOXA1 promoter with knockdown and expression profiling\",\n      \"pmids\": [\"28540746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposite H3K9me1/me2 effects mechanistically unexplained\", \"RARE-binding partner not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked KDM3B to cell-cycle progression and mitotic fidelity, showing loss causes spindle multipolarity and post-translational Cyclin D1 destabilization.\",\n      \"evidence\": \"CRISPR knockout in HepG2 with RNA-seq, flow cytometry, spindle imaging, and proteasome assays\",\n      \"pmids\": [\"30514438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking KDM3B to Cyclin D1 degradation undefined\", \"Direct vs indirect control of CDC123 not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that KDM3B catalytic activity is required for cancer cell proliferation and that it maintains chromatin compaction influencing oncoprotein stability.\",\n      \"evidence\": \"Catalytically-inactive rescue in CRPC cells with metabolomics; ChIP-seq/ATAC-seq and PML/RARα assays in NB4 APL cells\",\n      \"pmids\": [\"31822799\", \"31592194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demethylation targets driving metabolic gene loss not pinpointed\", \"Connection between chromatin accessibility and oncoprotein degradation mechanistically indirect\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened KDM3B function across autophagy activation, ferroptosis protection, and non-catalytic histone-supply control, showing both demethylase-dependent and chaperone-regulatory roles.\",\n      \"evidence\": \"ChIP and autophagic flux assays (HCT116); ATF4 co-IP and viability assays (HT-1080); tNASP and histone maturation assays\",\n      \"pmids\": [\"32716961\", \"32107878\", \"32070414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of tNASP level control unknown\", \"Whether ATF4 cooperation requires KDM3B catalysis not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a KDM3A/KDM3B complex sustaining pluripotency networks and revealed haploinsufficient roles in cerebellar plasticity, establishing functional partnership with its paralog.\",\n      \"evidence\": \"IP-MS and ChIP-seq in porcine iPSCs; heterozygous knockout mice with behavioral and epigenomic readouts\",\n      \"pmids\": [\"34042215\", \"34217333\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and architecture of the KDM3A/KDM3B complex unresolved\", \"Redundancy vs distinct functions of the two paralogs not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated KDM3B in protein quality control by influencing F508del-CFTR stability, proposing a non-histone lysine demethylation–ubiquitination link.\",\n      \"evidence\": \"siRNA demethylase library screen with CFTR stability and channel function assays\",\n      \"pmids\": [\"36077010\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Proposed CFTR lysine demethylation not confirmed by mutagenesis or structure\", \"Single knockdown screen result\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Delivered selective chemical probes and genetic evidence positioning KDM3B as a druggable dependency in fusion-driven rhabdomyosarcoma and mutant hematopoietic stem cells.\",\n      \"evidence\": \"NMR/SPR biophysical binding plus enzymatic and in vivo tumor assays for P3FI-90; CRISPR screens in IDH2/TET2-mutant HSPCs with JAK2 inhibition\",\n      \"pmids\": [\"38402212\", \"38819218\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-dependency with KDM1A mechanistically unexplained\", \"Whether HSPC fitness effect requires catalysis untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed in vivo that KDM3B loss bidirectionally redistributes H3K9 methylation to both silence and activate distinct gene sets, driving photoreceptor apoptosis.\",\n      \"evidence\": \"Conditional retinal knockout with scRNA-seq, CUT&TAG/ChIP-seq, ATAC-seq, and histology\",\n      \"pmids\": [\"39165843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of locus-specific gain vs loss of H3K9me unknown\", \"Direct vs secondary effects on apoptotic genes not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded KDM3B function into RNA biology and non-histone substrates: splicing regulation, m6A maintenance, immune evasion, and arginine demethylation of FEN1.\",\n      \"evidence\": \"Co-IP/MS with EFTUD2/PRMT5 and degron splicing analysis; RNA-IP linking KDM3B to LOX m6A; ChIP at SHP1 with STING/immune profiling; in vitro FEN1 R192 demethylation and PCNA-binding assays (preprint)\",\n      \"pmids\": [\"40510131\", \"40588066\", \"42201640\", \"41280084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splicing role mechanism beyond EFTUD2/PRMT5 association unclear\", \"FEN1 arginine demethylase activity awaits peer review and structural validation\", \"How KDM3B influences m6A deposition on LOX mRNA mechanistically undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KDM3B selects between catalytic histone demethylation, non-catalytic co-regulation, RNA-associated roles, and non-histone substrate demethylation in a given cellular context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating substrate range\", \"Rules governing locus- and context-specific recruitment unknown\", \"Relative physiological importance of each activity not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 6, 7, 16, 18, 20, 21]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 8, 11]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [17, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 6, 16]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 6, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 8, 18, 21]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [17, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"complexes\": [\"KDM3A/KDM3B complex\"],\n    \"partners\": [\"CBP\", \"SMRT\", \"ATF4\", \"OCT4\", \"SOX2\", \"KDM3A\", \"EFTUD2\", \"PRMT5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}