{"gene":"KDM4D","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2007,"finding":"KDM4D (JMJD2D) forms a complex with ligand-bound androgen receptor (AR) via its C-terminus, interacting with the AR ligand binding domain, and acts as a coactivator of AR transcriptional activity in a catalytic-activity-dependent manner.","method":"Co-immunoprecipitation, domain-mapping pulldown, luciferase reporter assay with catalytic mutants","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain mapping and functional validation by catalytic mutants, replicated across two family members","pmids":["17555712"],"is_preprint":false},{"year":2012,"finding":"KDM4D (JMJD2D) demethylates H3K9me3/me2 and H1.4K26 and forms a complex with p53 tumor suppressor (interacting with p53's DNA binding domain), coactivating p53 target gene p21 in a catalytic-activity-dependent manner.","method":"In vitro pulldown, co-immunoprecipitation, luciferase reporter with catalytic mutants, cell-based overexpression","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro domain mapping plus cell-based functional assay with catalytic mutants, multiple orthogonal methods","pmids":["22514644"],"is_preprint":false},{"year":2014,"finding":"KDM4D is rapidly recruited to DNA damage sites via its C-terminal region in a PARP1-dependent (but ATM-independent) manner; PARP1 ADP-ribosylates KDM4D after DNA damage, and KDM4D is required for efficient ATM substrate phosphorylation, chromatin association of ATM, Rad51 and p53BP1 foci formation, and both homology-directed repair and NHEJ.","method":"Live-cell imaging of laser-induced damage, co-immunoprecipitation, siRNA knockdown with functional DSB repair assays, domain mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (live imaging, Co-IP, repair assays, ADP-ribosylation), single lab but strong mechanistic dissection","pmids":["24550317"],"is_preprint":false},{"year":2014,"finding":"KDM4D binds RNA via two non-canonical RNA-binding domains (N-terminal aa 115-236 and C-terminal aa 348-523), independent of its demethylase activity; RNA interaction of the N-terminal region is required for KDM4D chromatin association and subsequent H3K9me3 demethylation in cells.","method":"RNA-binding assays, domain-deletion mapping, chromatin fractionation, H3K9me3 immunofluorescence in KDM4D mutant-expressing cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — domain mapping with functional consequence on chromatin localization and histone demethylation, multiple orthogonal methods","pmids":["25378304"],"is_preprint":false},{"year":2015,"finding":"KDM4D binds poly(ADP-ribose) (PAR) in vitro via its C-terminal region, and this KDM4D-RNA interaction is also required for KDM4D accumulation at DNA breakage sites.","method":"In vitro PAR binding assay, live-cell imaging at laser-induced damage sites, RNA interaction domain mutants","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro PAR binding plus live imaging, single lab follow-up to PMID:24550317","pmids":["25714495"],"is_preprint":false},{"year":2016,"finding":"KDM4D demethylates H3K9me3 at DNA replication origins, interacts with replication proteins, and its recruitment depends on pre-replicative complex components ORC and MCM; KDM4D depletion impairs loading of Cdc45, PCNA, and polymerase δ but not ORC/MCM, demonstrating a role in pre-initiative complex formation for DNA replication.","method":"siRNA knockdown, H3K9M rescue experiment, co-immunoprecipitation with replication proteins, ChIP at origins, replication assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 — epistasis-style H3K9M rescue plus Co-IP and ChIP, multiple orthogonal methods establishing pathway position","pmids":["27679476"],"is_preprint":false},{"year":2017,"finding":"KDM4D was identified as a potential demethylase of H3K79me3 using chemically synthesized trimethylated H3K79 as substrate in an in vitro demethylase assay.","method":"Total chemical synthesis of H3K79me3 histone; in vitro demethylase activity assay","journal":"Bioorganic & medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution with synthetic substrate, but single lab and described as 'potential', limited follow-up","pmids":["28434780"],"is_preprint":false},{"year":2018,"finding":"KDM4D (JMJD2D) physically interacts with β-catenin and demethylates H3K9me3 at promoters of β-catenin target genes (MYC, CCND1, MMP2, MMP9) to activate their transcription and promote colorectal cancer cell proliferation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, promoter-luciferase assay, KO mouse models","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ChIP, promoter activity, and in vivo KO models provide strong multi-method evidence","pmids":["30472235"],"is_preprint":false},{"year":2018,"finding":"KDM4D directly interacts with the HIF1β gene promoter and activates HIF1β expression via H3K9me3 and H3K36me3 demethylation, promoting VEGFA-dependent tumor angiogenesis.","method":"ChIP assay, luciferase reporter, siRNA knockdown, in vitro and in vivo tumor models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter with functional tumor readout, single lab","pmids":["30060750"],"is_preprint":false},{"year":2018,"finding":"KDM4D catalyzes H3K9 di- and tri-demethylation to promote TLR4 expression in hepatic stellate cells, subsequently activating NF-κB signaling and liver fibrogenesis.","method":"siRNA knockdown, ChIP, transcriptome analysis, in vivo CCl4 fibrosis model","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus in vivo model, single lab","pmids":["30527625"],"is_preprint":false},{"year":2020,"finding":"KDM4D (JMJD2D) interacts with Gli2 and reduces H3K9me3 levels at Hedgehog target gene promoters to promote their expression, facilitating colonic regeneration and tumorigenesis.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, JMJD2D-KO mouse colitis model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ChIP, and in vivo KO model with multiple orthogonal methods","pmids":["32094404"],"is_preprint":false},{"year":2020,"finding":"KDM4D (JMJD2D) activates HIF1 signaling through three mechanisms: (1) cooperating with SOX9 to enhance mTOR expression and HIF1α translation; (2) cooperating with c-Fos to enhance HIF1β transcription; (3) interacting with HIF1α to enhance glycolytic gene expression; all dependent on demethylase activity.","method":"siRNA knockdown, rescue overexpression experiments, ChIP, demethylase-defective mutant analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanistic arms tested with catalytic mutant, single lab","pmids":["32989255"],"is_preprint":false},{"year":2020,"finding":"KDM4D (JMJD2D) promotes liver cancer stem cell self-renewal by reducing H3K9me3 at the EpCAM promoter via interaction with β-catenin/TCF4, and at the Sox9 promoter via interaction with Notch1 intracellular domain.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, shRNA knockdown, rescue experiments, in vivo xenograft","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP with in vivo validation, single lab","pmids":["33434575"],"is_preprint":false},{"year":2020,"finding":"KDM4D (JMJD2D) directly interacts with p53 and inhibits p53 recruitment to the p21 and PUMA promoters in a demethylase-activity-independent manner, acting as a novel p53 antagonist to promote liver cancer.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, EMSA, shRNA knockdown, KO mouse DEN-induced liver cancer model","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ChIP, EMSA, and in vivo KO model, multiple orthogonal methods establishing demethylase-independent mechanism","pmids":["32754284"],"is_preprint":false},{"year":2020,"finding":"KDM4D interacts with NFIB and MLL1 complex; KDM4D-mediated demethylation of H3K9me3 at PPARγ and C/EBPα promoters is required for NFIB and MLL1 complex to deposit H3K4me3 and activate adipogenic gene expression, acting upstream of these activators.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, rescue by exogenous expression in C3H10T1/2 cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP with functional epistasis, single lab","pmids":["32080306"],"is_preprint":false},{"year":2021,"finding":"KDM4D transcriptionally activates SYVN1 (an E3 ubiquitin ligase) via H3K9me3 demethylation at its promoter, which then triggers ubiquitin-dependent degradation of HMGB1, suppressing esophageal squamous cell carcinoma progression.","method":"ChIP, in vitro ubiquitination assay, shRNA knockdown, in vivo xenograft","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and ubiquitination assay establish the mechanistic chain, single lab","pmids":["34820329"],"is_preprint":false},{"year":2021,"finding":"KDM4D demethylates H3K9me3 at the MCL-1 promoter to promote MCL-1 expression in acute myeloid leukemia cells.","method":"ChIP, siRNA knockdown, cell proliferation and apoptosis assays","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP with functional KD phenotype, single lab","pmids":["34017391"],"is_preprint":false},{"year":2021,"finding":"KDM4D directly interacts with the JAG1 promoter and upregulates VEGFR-3 expression to promote tumor angiogenesis in clear cell renal cell carcinoma.","method":"ChIP, siRNA knockdown, in vitro angiogenesis assay, in vivo xenograft","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 — ChIP with functional assay but limited mechanistic detail on direct mechanism, single lab","pmids":["34667158"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of KDM4D in complex with two inhibitors (OWS and 10r) at 2.0 Å resolution revealed inhibitor binding modes within the active site and a loop movement that blocks the histone-binding site upon ligand binding.","method":"X-ray crystallography at 2.0 Å","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with defined resolution providing structural basis of inhibition","pmids":["33780862"],"is_preprint":false},{"year":2022,"finding":"TRIM14 recruits deubiquitinases USP14 and BRCC3 to cleave K63-linked ubiquitin chains on KDM4D, preventing KDM4D from undergoing OPTN-mediated selective autophagy, thereby stabilizing KDM4D and sustaining H3K9me3 demethylation and proinflammatory cytokine (IL-12, IL-23) expression.","method":"Co-immunoprecipitation, ubiquitination assay, autophagy flux assay, dendritic cell KO models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ubiquitination assay, and in vivo KO model with multiple orthogonal methods establishing the regulatory axis","pmids":["35145029"],"is_preprint":false},{"year":2022,"finding":"KDM4D (JMJD2D) coactivates SP-1 to promote IFNGR1 expression, which elevates STAT3-IRF1 signaling; JMJD2D also acts as a coactivator for the STAT3-IRF1 axis to enhance PD-L1 transcription in a demethylation-activity-dependent manner.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, demethylase-mutant rescue, in vivo tumor models with CD8+ T cell infiltration analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP with in vivo tumor immunology readout, single lab","pmids":["35027670"],"is_preprint":false},{"year":2023,"finding":"SET7/9 methylates KDM4D (JMJD2D) on K427; mutation of K427 reduces prostate cancer cell growth, invasion, and tumor formation, and alters transcription of downstream targets including CBLC and PLAGL1.","method":"In vitro methylation assay, site-directed mutagenesis (K427R), cell invasion and tumor growth assays, transcriptomic analysis","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro methylation plus mutagenesis with functional cellular phenotype, single lab","pmids":["38045004"],"is_preprint":false},{"year":2023,"finding":"KDM4D (JMJD2D) stabilizes HBx protein by suppressing TRIM14-mediated ubiquitin-proteasome degradation, and acts as a co-activator of HBx on cccDNA to augment HBV transcription and replication.","method":"Co-immunoprecipitation, ubiquitylation assay, ChIP on cccDNA, siRNA knockdown in HBV-infected cells, KO mouse HBV model","journal":"JHEP reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, ubiquitination, ChIP, and in vivo KO model, multiple orthogonal methods","pmids":["37701334"],"is_preprint":false},{"year":2023,"finding":"KDM4D cooperates with STAT3 and is recruited to the IL-17F promoter to demethylate H3K9me3, inducing IL-17F expression and subsequently β-defensin expression for host defense against enteric bacterial infection.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, JMJD2D-KO mouse Citrobacter rodentium infection model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP with in vivo KO infection model, single lab","pmids":["38905308"],"is_preprint":false},{"year":2023,"finding":"KDM4D is a positive regulator of type I interferon responses; it is pre-associated with enhancer regions and redistributes to inducible promoters upon stimulation, promoting enhancer RNA transcription and dynamic H3K9me2 demethylation at associated promoters.","method":"Knockdown and overexpression in MEFs, epigenomic analyses (ChIP-seq, RNA-seq), viral susceptibility assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — epigenomics plus functional viral susceptibility readout, single lab","pmids":["37275914"],"is_preprint":false},{"year":2024,"finding":"X-ray crystal structures of KDM4D bound to novel inhibitors (tetrazole and pyridine core compounds) revealed that flexible tails probe distal residues in the histone-binding site and a prominent loop movement blocks histone-binding site accessibility upon ligand binding.","method":"X-ray crystallography","journal":"European journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structures with multiple novel compounds providing structural mapping of binding site","pmids":["38981336"],"is_preprint":false},{"year":2024,"finding":"KDM4D is required for male fertility; Kdm4d mutant male mice show impaired sperm motility and subfertility, associated with altered H3K9me3 distribution in round spermatids, demonstrating KDM4D-mediated H3K9me3 adjustment is needed for motile sperm generation.","method":"Kdm4d KO mouse generation, sperm motility assay, H3K9me3 immunofluorescence in spermatids","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype and histone mark readout, single lab","pmids":["39034148"],"is_preprint":false},{"year":2024,"finding":"KDM4D's H3K9me3 demethylase activity is iron-dependent; under iron deficiency, KDM4D activity decreases, increasing H3K9me3 at the PIK3R3 promoter, suppressing PIK3R3 expression and inhibiting quiescent MSC activation via the PI3K-Akt-Foxo1 pathway.","method":"Iron chelation experiments, ChIP at PIK3R3 promoter, PI3K-Akt-Foxo1 pathway rescue, iron-deficient mouse model with bone mass measurement","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and pathway rescue with in vivo model, single lab","pmids":["39158700"],"is_preprint":false},{"year":2023,"finding":"KDM4D binds RPS5 physically via a specific structural domain and the KDM4D-RPS5 complex promotes osteo/dentinogenic differentiation of stem cells of the apical papilla; ChIP showed KDM4D demethylates H3K9me2/me3 at the CNR1 promoter, and disruption of the KDM4D-RPS5 binding abolishes differentiation.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, overexpression, alizarin red staining","journal":"Oral diseases","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ChIP with functional differentiation readout, single lab","pmids":["36579641"],"is_preprint":false}],"current_model":"KDM4D (JMJD2D) is a JmjC-domain histone demethylase that removes di- and tri-methyl marks from H3K9 (and potentially H3K79me3 and H1.4K26) in an iron- and 2-oxoglutarate-dependent manner; it is recruited to chromatin via RNA interactions and to DNA damage sites via PARP1-mediated ADP-ribosylation and PAR binding, where it facilitates DSB repair; it coactivates multiple transcription factors (AR, p53, β-catenin, Gli2, HIF1α, STAT3-IRF1, HBx) by demethylating repressive H3K9me3 at target promoters, while also acting as a demethylase-independent antagonist of p53; its stability is regulated by the TRIM14-USP14-BRCC3 deubiquitinase complex that prevents OPTN-mediated autophagic degradation, and it is further post-translationally regulated by SET7/9-mediated methylation on K427."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing that KDM4D functions as a transcriptional coactivator resolved how this demethylase connects to gene regulation: it physically associates with ligand-bound androgen receptor and stimulates AR-dependent transcription in a catalytic-activity-dependent manner.","evidence":"Co-immunoprecipitation with domain mapping and luciferase reporter assays with catalytic mutants in cell lines","pmids":["17555712"],"confidence":"High","gaps":["Whether coactivation extends to other nuclear receptors beyond AR","Genome-wide target identification not performed","Structural basis of the AR–KDM4D interaction undefined"]},{"year":2012,"claim":"Demonstrating KDM4D interaction with p53 and coactivation of p21 expanded its coactivator repertoire beyond nuclear receptors to tumor suppressors and established dual substrate specificity for H3K9me3/me2 and H1.4K26.","evidence":"In vitro pulldown, co-immunoprecipitation, and luciferase reporter assays with catalytic mutants","pmids":["22514644"],"confidence":"High","gaps":["Whether KDM4D–p53 interaction is activating or inhibitory in vivo remained unresolved until later work","H1.4K26 demethylation relevance in endogenous chromatin not tested"]},{"year":2014,"claim":"Discovering that KDM4D is rapidly recruited to DNA damage sites via PARP1-mediated ADP-ribosylation and is required for ATM activation, Rad51/53BP1 foci, and both HR and NHEJ revealed a non-transcriptional chromatin-modifying role in the DNA damage response.","evidence":"Live-cell laser microirradiation imaging, co-immunoprecipitation, siRNA knockdown with DR-GFP and EJ5 repair assays","pmids":["24550317"],"confidence":"High","gaps":["Whether demethylase activity is required at damage sites or whether the role is structural","Identity of specific H3K9me3-marked loci altered at damage sites unknown"]},{"year":2014,"claim":"Identifying two non-canonical RNA-binding domains in KDM4D and showing that N-terminal RNA binding is required for chromatin association established RNA interaction as a prerequisite for KDM4D's epigenetic function.","evidence":"RNA-binding assays, domain-deletion mapping, chromatin fractionation, and H3K9me3 immunofluorescence","pmids":["25378304"],"confidence":"High","gaps":["Identity of specific RNA species that recruit KDM4D to chromatin unknown","Whether RNA binding is locus-specific or generic not determined"]},{"year":2015,"claim":"Showing that KDM4D directly binds poly(ADP-ribose) via its C-terminal region linked the RNA-binding and DNA-damage-recruitment functions, explaining how PARP1 activity recruits KDM4D to break sites.","evidence":"In vitro PAR binding assay and live-cell imaging at laser-induced damage sites with RNA-binding domain mutants","pmids":["25714495"],"confidence":"Medium","gaps":["Whether PAR binding and RNA binding compete for the same C-terminal surface not resolved","In vivo PAR-binding confirmation lacking"]},{"year":2016,"claim":"Placing KDM4D at DNA replication origins downstream of ORC/MCM but upstream of Cdc45/PCNA loading revealed a replication-licensing function, demonstrating that H3K9me3 removal is a prerequisite for pre-initiation complex assembly.","evidence":"siRNA knockdown, H3K9M rescue epistasis, co-immunoprecipitation with replication proteins, and ChIP at origins","pmids":["27679476"],"confidence":"High","gaps":["How KDM4D is selectively targeted to active origins versus silent ones","Whether this role is cell-cycle-phase restricted"]},{"year":2018,"claim":"Multiple studies converged to show KDM4D acts as a coactivator for β-catenin/Wnt and HIF1 pathways by demethylating H3K9me3 at target promoters, establishing it as a broad oncogenic transcriptional coactivator in solid tumors.","evidence":"Co-immunoprecipitation, ChIP, promoter-luciferase assays, Kdm4d KO mouse models (colorectal cancer), and tumor xenografts","pmids":["30472235","30060750","32989255"],"confidence":"High","gaps":["Whether KDM4D recruitment to Wnt versus HIF targets involves distinct adaptor proteins","Relative contribution of demethylase-dependent versus -independent activities in tumors"]},{"year":2020,"claim":"Discovering that KDM4D inhibits p53 recruitment to target promoters independently of its demethylase activity resolved the earlier paradox of KDM4D both coactivating and antagonizing p53, revealing a dual mechanism with opposing transcriptional outcomes.","evidence":"Co-immunoprecipitation, ChIP, EMSA, and Kdm4d KO mouse DEN-induced liver cancer model","pmids":["32754284"],"confidence":"High","gaps":["Structural basis for demethylase-independent p53 sequestration not determined","Whether this mechanism operates in non-hepatic tissues"]},{"year":2020,"claim":"Identification of KDM4D interactions with Gli2 (Hedgehog) and Notch1-ICD/β-catenin-TCF4 further broadened the signaling pathways coactivated by KDM4D, linking it to intestinal regeneration and cancer stem cell self-renewal.","evidence":"Co-immunoprecipitation, ChIP, Kdm4d KO mouse colitis model, shRNA knockdown with xenograft","pmids":["32094404","33434575"],"confidence":"High","gaps":["Whether KDM4D binds Gli2 and Notch1-ICD simultaneously or in a mutually exclusive manner","No genome-wide binding profile under Hedgehog/Notch stimulation"]},{"year":2021,"claim":"Crystal structures of KDM4D with active-site inhibitors at 2.0 Å resolution revealed a ligand-induced loop movement that occludes the histone-binding channel, providing a structural framework for selective inhibitor design.","evidence":"X-ray crystallography at 2.0 Å resolution with two distinct inhibitor scaffolds","pmids":["33780862"],"confidence":"High","gaps":["No co-crystal structure with histone peptide substrate for comparison","In vivo efficacy of these inhibitors not reported"]},{"year":2022,"claim":"Elucidation of the TRIM14–USP14/BRCC3 deubiquitination axis that prevents K63-linked ubiquitin-mediated autophagic degradation of KDM4D by OPTN revealed how KDM4D protein stability is regulated post-translationally to sustain proinflammatory cytokine production.","evidence":"Co-immunoprecipitation, ubiquitination assays, autophagy flux assays, and dendritic cell-specific KO models","pmids":["35145029"],"confidence":"High","gaps":["Which E3 ligase attaches the K63-linked chains to KDM4D not identified","Whether this regulatory axis operates outside dendritic cells"]},{"year":2023,"claim":"Discovery of SET7/9-mediated methylation of KDM4D at K427 that modulates its oncogenic activity added a non-histone methylation regulatory layer, showing that KDM4D is itself a methylation substrate with functional consequences.","evidence":"In vitro methylation assay, K427R mutagenesis, cell invasion and tumor growth assays, transcriptomics","pmids":["38045004"],"confidence":"Medium","gaps":["How K427 methylation affects demethylase catalytic activity or protein interactions is mechanistically unclear","No structural basis for K427 methylation effect","Single lab, not independently confirmed"]},{"year":2023,"claim":"Showing KDM4D pre-associates with enhancer regions and dynamically redistributes to inducible promoters upon innate immune stimulation to demethylate H3K9me2 and drive enhancer RNA transcription established a role in type I interferon responses.","evidence":"ChIP-seq, RNA-seq, knockdown/overexpression in MEFs, viral susceptibility assay","pmids":["37275914"],"confidence":"Medium","gaps":["Identity of the signal that triggers KDM4D redistribution from enhancers to promoters","Whether this enhancer-priming role extends to other innate immune stimuli beyond IFN","Single lab"]},{"year":2024,"claim":"Demonstrating that Kdm4d KO male mice have impaired sperm motility and altered H3K9me3 distribution in round spermatids established a physiological requirement for KDM4D in male fertility beyond its oncological context.","evidence":"Kdm4d KO mouse, sperm motility assay, H3K9me3 immunofluorescence in spermatids","pmids":["39034148"],"confidence":"Medium","gaps":["Specific genomic loci where H3K9me3 is aberrantly retained in KO spermatids not mapped","Whether the fertility defect is cell-autonomous in germ cells","Single lab, not independently confirmed"]},{"year":null,"claim":"Key unresolved questions include the identity of RNA species that recruit KDM4D to specific chromatin loci, the E3 ubiquitin ligase responsible for K63-linked ubiquitination of KDM4D, the structural basis for its demethylase-independent p53-antagonist function, and whether its diverse coactivator interactions are competitive or combinatorial at individual promoters.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide binding analysis under multiple simultaneous signaling inputs","Structural basis of KDM4D–transcription factor interfaces unresolved","In vivo relevance of H3K79me3 demethylation activity not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,5,7,8,9,10,11,12,14,15,16,24,26,27,28]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[1,6,7,9,27]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3,4]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,7,10,11,13,20]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[1,5,7,10,24]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,3,5,7,10,24]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,5,24,26]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,7,10,11,20,24]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,5,7,9,10,14,24,26]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,9,10,11,20,27]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,23,24]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[19]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,10,12,13,16,17,20]}],"complexes":[],"partners":["AR","TP53","CTNNB1","GLI2","PARP1","STAT3","TRIM14","HIF1A"],"other_free_text":[]},"mechanistic_narrative":"KDM4D (JMJD2D) is a JmjC-domain histone demethylase that removes repressive H3K9me2/me3 marks in an iron- and 2-oxoglutarate-dependent manner, functioning as a transcriptional coactivator for diverse signaling pathways and as a facilitator of DNA damage repair and replication origin licensing. KDM4D is recruited to chromatin through RNA-binding domains and to DNA double-strand break sites via PARP1-dependent ADP-ribosylation and poly(ADP-ribose) binding, where it promotes ATM activation, Rad51 and 53BP1 focus formation, and both homologous recombination and non-homologous end joining [PMID:24550317, PMID:25714495]. It physically interacts with and coactivates multiple transcription factors—including AR, β-catenin, Gli2, HIF1α, STAT3, and p53—by demethylating H3K9me3 at their target promoters, while also antagonizing p53 transcriptional activity through a demethylase-independent mechanism that blocks p53 promoter recruitment [PMID:17555712, PMID:30472235, PMID:32094404, PMID:32754284]. KDM4D protein stability is regulated by TRIM14-recruited deubiquitinases USP14 and BRCC3, which remove K63-linked ubiquitin chains to prevent OPTN-mediated autophagic degradation, and its activity is further modulated by SET7/9-mediated methylation at K427 [PMID:35145029, PMID:38045004]."},"prefetch_data":{"uniprot":{"accession":"Q6B0I6","full_name":"Lysine-specific demethylase 4D","aliases":["JmjC domain-containing histone demethylation protein 3D","Jumonji domain-containing protein 2D","[histone H3]-trimethyl-L-lysine(9) demethylase 4D"],"length_aa":523,"mass_kda":58.6,"function":"Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Demethylates both di- and trimethylated H3 'Lys-9' residue, while it has no activity on monomethylated residues. Demethylation of Lys residue generates formaldehyde and succinate","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6B0I6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM4D","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KDM4D","total_profiled":1310},"omim":[{"mim_id":"609766","title":"LYSINE DEMETHYLASE 4D; KDM4D","url":"https://www.omim.org/entry/609766"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":31.1}],"url":"https://www.proteinatlas.org/search/KDM4D"},"hgnc":{"alias_symbol":["FLJ10251"],"prev_symbol":["JMJD2D"]},"alphafold":{"accession":"Q6B0I6","domains":[{"cath_id":"2.60.120.650","chopping":"20-366","consensus_level":"high","plddt":90.6904,"start":20,"end":366}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6B0I6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6B0I6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6B0I6-F1-predicted_aligned_error_v6.png","plddt_mean":73.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM4D","jax_strain_url":"https://www.jax.org/strain/search?query=KDM4D"},"sequence":{"accession":"Q6B0I6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6B0I6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6B0I6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6B0I6"}},"corpus_meta":[{"pmid":"17555712","id":"PMC_17555712","title":"Activation 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with the AR ligand binding domain, and acts as a coactivator of AR transcriptional activity in a catalytic-activity-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping pulldown, luciferase reporter assay with catalytic mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping and functional validation by catalytic mutants, replicated across two family members\",\n      \"pmids\": [\"17555712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM4D (JMJD2D) demethylates H3K9me3/me2 and H1.4K26 and forms a complex with p53 tumor suppressor (interacting with p53's DNA binding domain), coactivating p53 target gene p21 in a catalytic-activity-dependent manner.\",\n      \"method\": \"In vitro pulldown, co-immunoprecipitation, luciferase reporter with catalytic mutants, cell-based overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro domain mapping plus cell-based functional assay with catalytic mutants, multiple orthogonal methods\",\n      \"pmids\": [\"22514644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM4D is rapidly recruited to DNA damage sites via its C-terminal region in a PARP1-dependent (but ATM-independent) manner; PARP1 ADP-ribosylates KDM4D after DNA damage, and KDM4D is required for efficient ATM substrate phosphorylation, chromatin association of ATM, Rad51 and p53BP1 foci formation, and both homology-directed repair and NHEJ.\",\n      \"method\": \"Live-cell imaging of laser-induced damage, co-immunoprecipitation, siRNA knockdown with functional DSB repair assays, domain mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (live imaging, Co-IP, repair assays, ADP-ribosylation), single lab but strong mechanistic dissection\",\n      \"pmids\": [\"24550317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM4D binds RNA via two non-canonical RNA-binding domains (N-terminal aa 115-236 and C-terminal aa 348-523), independent of its demethylase activity; RNA interaction of the N-terminal region is required for KDM4D chromatin association and subsequent H3K9me3 demethylation in cells.\",\n      \"method\": \"RNA-binding assays, domain-deletion mapping, chromatin fractionation, H3K9me3 immunofluorescence in KDM4D mutant-expressing cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping with functional consequence on chromatin localization and histone demethylation, multiple orthogonal methods\",\n      \"pmids\": [\"25378304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KDM4D binds poly(ADP-ribose) (PAR) in vitro via its C-terminal region, and this KDM4D-RNA interaction is also required for KDM4D accumulation at DNA breakage sites.\",\n      \"method\": \"In vitro PAR binding assay, live-cell imaging at laser-induced damage sites, RNA interaction domain mutants\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro PAR binding plus live imaging, single lab follow-up to PMID:24550317\",\n      \"pmids\": [\"25714495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM4D demethylates H3K9me3 at DNA replication origins, interacts with replication proteins, and its recruitment depends on pre-replicative complex components ORC and MCM; KDM4D depletion impairs loading of Cdc45, PCNA, and polymerase δ but not ORC/MCM, demonstrating a role in pre-initiative complex formation for DNA replication.\",\n      \"method\": \"siRNA knockdown, H3K9M rescue experiment, co-immunoprecipitation with replication proteins, ChIP at origins, replication assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis-style H3K9M rescue plus Co-IP and ChIP, multiple orthogonal methods establishing pathway position\",\n      \"pmids\": [\"27679476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM4D was identified as a potential demethylase of H3K79me3 using chemically synthesized trimethylated H3K79 as substrate in an in vitro demethylase assay.\",\n      \"method\": \"Total chemical synthesis of H3K79me3 histone; in vitro demethylase activity assay\",\n      \"journal\": \"Bioorganic & medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with synthetic substrate, but single lab and described as 'potential', limited follow-up\",\n      \"pmids\": [\"28434780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM4D (JMJD2D) physically interacts with β-catenin and demethylates H3K9me3 at promoters of β-catenin target genes (MYC, CCND1, MMP2, MMP9) to activate their transcription and promote colorectal cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, promoter-luciferase assay, KO mouse models\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, promoter activity, and in vivo KO models provide strong multi-method evidence\",\n      \"pmids\": [\"30472235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM4D directly interacts with the HIF1β gene promoter and activates HIF1β expression via H3K9me3 and H3K36me3 demethylation, promoting VEGFA-dependent tumor angiogenesis.\",\n      \"method\": \"ChIP assay, luciferase reporter, siRNA knockdown, in vitro and in vivo tumor models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter with functional tumor readout, single lab\",\n      \"pmids\": [\"30060750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM4D catalyzes H3K9 di- and tri-demethylation to promote TLR4 expression in hepatic stellate cells, subsequently activating NF-κB signaling and liver fibrogenesis.\",\n      \"method\": \"siRNA knockdown, ChIP, transcriptome analysis, in vivo CCl4 fibrosis model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus in vivo model, single lab\",\n      \"pmids\": [\"30527625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4D (JMJD2D) interacts with Gli2 and reduces H3K9me3 levels at Hedgehog target gene promoters to promote their expression, facilitating colonic regeneration and tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, JMJD2D-KO mouse colitis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, and in vivo KO model with multiple orthogonal methods\",\n      \"pmids\": [\"32094404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4D (JMJD2D) activates HIF1 signaling through three mechanisms: (1) cooperating with SOX9 to enhance mTOR expression and HIF1α translation; (2) cooperating with c-Fos to enhance HIF1β transcription; (3) interacting with HIF1α to enhance glycolytic gene expression; all dependent on demethylase activity.\",\n      \"method\": \"siRNA knockdown, rescue overexpression experiments, ChIP, demethylase-defective mutant analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanistic arms tested with catalytic mutant, single lab\",\n      \"pmids\": [\"32989255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4D (JMJD2D) promotes liver cancer stem cell self-renewal by reducing H3K9me3 at the EpCAM promoter via interaction with β-catenin/TCF4, and at the Sox9 promoter via interaction with Notch1 intracellular domain.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, shRNA knockdown, rescue experiments, in vivo xenograft\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP with in vivo validation, single lab\",\n      \"pmids\": [\"33434575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4D (JMJD2D) directly interacts with p53 and inhibits p53 recruitment to the p21 and PUMA promoters in a demethylase-activity-independent manner, acting as a novel p53 antagonist to promote liver cancer.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, EMSA, shRNA knockdown, KO mouse DEN-induced liver cancer model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP, EMSA, and in vivo KO model, multiple orthogonal methods establishing demethylase-independent mechanism\",\n      \"pmids\": [\"32754284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4D interacts with NFIB and MLL1 complex; KDM4D-mediated demethylation of H3K9me3 at PPARγ and C/EBPα promoters is required for NFIB and MLL1 complex to deposit H3K4me3 and activate adipogenic gene expression, acting upstream of these activators.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, rescue by exogenous expression in C3H10T1/2 cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP with functional epistasis, single lab\",\n      \"pmids\": [\"32080306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4D transcriptionally activates SYVN1 (an E3 ubiquitin ligase) via H3K9me3 demethylation at its promoter, which then triggers ubiquitin-dependent degradation of HMGB1, suppressing esophageal squamous cell carcinoma progression.\",\n      \"method\": \"ChIP, in vitro ubiquitination assay, shRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and ubiquitination assay establish the mechanistic chain, single lab\",\n      \"pmids\": [\"34820329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4D demethylates H3K9me3 at the MCL-1 promoter to promote MCL-1 expression in acute myeloid leukemia cells.\",\n      \"method\": \"ChIP, siRNA knockdown, cell proliferation and apoptosis assays\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with functional KD phenotype, single lab\",\n      \"pmids\": [\"34017391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4D directly interacts with the JAG1 promoter and upregulates VEGFR-3 expression to promote tumor angiogenesis in clear cell renal cell carcinoma.\",\n      \"method\": \"ChIP, siRNA knockdown, in vitro angiogenesis assay, in vivo xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — ChIP with functional assay but limited mechanistic detail on direct mechanism, single lab\",\n      \"pmids\": [\"34667158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of KDM4D in complex with two inhibitors (OWS and 10r) at 2.0 Å resolution revealed inhibitor binding modes within the active site and a loop movement that blocks the histone-binding site upon ligand binding.\",\n      \"method\": \"X-ray crystallography at 2.0 Å\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with defined resolution providing structural basis of inhibition\",\n      \"pmids\": [\"33780862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM14 recruits deubiquitinases USP14 and BRCC3 to cleave K63-linked ubiquitin chains on KDM4D, preventing KDM4D from undergoing OPTN-mediated selective autophagy, thereby stabilizing KDM4D and sustaining H3K9me3 demethylation and proinflammatory cytokine (IL-12, IL-23) expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, autophagy flux assay, dendritic cell KO models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination assay, and in vivo KO model with multiple orthogonal methods establishing the regulatory axis\",\n      \"pmids\": [\"35145029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM4D (JMJD2D) coactivates SP-1 to promote IFNGR1 expression, which elevates STAT3-IRF1 signaling; JMJD2D also acts as a coactivator for the STAT3-IRF1 axis to enhance PD-L1 transcription in a demethylation-activity-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, demethylase-mutant rescue, in vivo tumor models with CD8+ T cell infiltration analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP with in vivo tumor immunology readout, single lab\",\n      \"pmids\": [\"35027670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SET7/9 methylates KDM4D (JMJD2D) on K427; mutation of K427 reduces prostate cancer cell growth, invasion, and tumor formation, and alters transcription of downstream targets including CBLC and PLAGL1.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis (K427R), cell invasion and tumor growth assays, transcriptomic analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro methylation plus mutagenesis with functional cellular phenotype, single lab\",\n      \"pmids\": [\"38045004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM4D (JMJD2D) stabilizes HBx protein by suppressing TRIM14-mediated ubiquitin-proteasome degradation, and acts as a co-activator of HBx on cccDNA to augment HBV transcription and replication.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, ChIP on cccDNA, siRNA knockdown in HBV-infected cells, KO mouse HBV model\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ubiquitination, ChIP, and in vivo KO model, multiple orthogonal methods\",\n      \"pmids\": [\"37701334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM4D cooperates with STAT3 and is recruited to the IL-17F promoter to demethylate H3K9me3, inducing IL-17F expression and subsequently β-defensin expression for host defense against enteric bacterial infection.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, JMJD2D-KO mouse Citrobacter rodentium infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP with in vivo KO infection model, single lab\",\n      \"pmids\": [\"38905308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM4D is a positive regulator of type I interferon responses; it is pre-associated with enhancer regions and redistributes to inducible promoters upon stimulation, promoting enhancer RNA transcription and dynamic H3K9me2 demethylation at associated promoters.\",\n      \"method\": \"Knockdown and overexpression in MEFs, epigenomic analyses (ChIP-seq, RNA-seq), viral susceptibility assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epigenomics plus functional viral susceptibility readout, single lab\",\n      \"pmids\": [\"37275914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"X-ray crystal structures of KDM4D bound to novel inhibitors (tetrazole and pyridine core compounds) revealed that flexible tails probe distal residues in the histone-binding site and a prominent loop movement blocks histone-binding site accessibility upon ligand binding.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"European journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structures with multiple novel compounds providing structural mapping of binding site\",\n      \"pmids\": [\"38981336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM4D is required for male fertility; Kdm4d mutant male mice show impaired sperm motility and subfertility, associated with altered H3K9me3 distribution in round spermatids, demonstrating KDM4D-mediated H3K9me3 adjustment is needed for motile sperm generation.\",\n      \"method\": \"Kdm4d KO mouse generation, sperm motility assay, H3K9me3 immunofluorescence in spermatids\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype and histone mark readout, single lab\",\n      \"pmids\": [\"39034148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM4D's H3K9me3 demethylase activity is iron-dependent; under iron deficiency, KDM4D activity decreases, increasing H3K9me3 at the PIK3R3 promoter, suppressing PIK3R3 expression and inhibiting quiescent MSC activation via the PI3K-Akt-Foxo1 pathway.\",\n      \"method\": \"Iron chelation experiments, ChIP at PIK3R3 promoter, PI3K-Akt-Foxo1 pathway rescue, iron-deficient mouse model with bone mass measurement\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and pathway rescue with in vivo model, single lab\",\n      \"pmids\": [\"39158700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM4D binds RPS5 physically via a specific structural domain and the KDM4D-RPS5 complex promotes osteo/dentinogenic differentiation of stem cells of the apical papilla; ChIP showed KDM4D demethylates H3K9me2/me3 at the CNR1 promoter, and disruption of the KDM4D-RPS5 binding abolishes differentiation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, overexpression, alizarin red staining\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ChIP with functional differentiation readout, single lab\",\n      \"pmids\": [\"36579641\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM4D (JMJD2D) is a JmjC-domain histone demethylase that removes di- and tri-methyl marks from H3K9 (and potentially H3K79me3 and H1.4K26) in an iron- and 2-oxoglutarate-dependent manner; it is recruited to chromatin via RNA interactions and to DNA damage sites via PARP1-mediated ADP-ribosylation and PAR binding, where it facilitates DSB repair; it coactivates multiple transcription factors (AR, p53, β-catenin, Gli2, HIF1α, STAT3-IRF1, HBx) by demethylating repressive H3K9me3 at target promoters, while also acting as a demethylase-independent antagonist of p53; its stability is regulated by the TRIM14-USP14-BRCC3 deubiquitinase complex that prevents OPTN-mediated autophagic degradation, and it is further post-translationally regulated by SET7/9-mediated methylation on K427.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KDM4D (JMJD2D) is a JmjC-domain histone demethylase that removes repressive H3K9me2/me3 marks in an iron- and 2-oxoglutarate-dependent manner, functioning as a transcriptional coactivator for diverse signaling pathways and as a facilitator of DNA damage repair and replication origin licensing. KDM4D is recruited to chromatin through RNA-binding domains and to DNA double-strand break sites via PARP1-dependent ADP-ribosylation and poly(ADP-ribose) binding, where it promotes ATM activation, Rad51 and 53BP1 focus formation, and both homologous recombination and non-homologous end joining [PMID:24550317, PMID:25714495]. It physically interacts with and coactivates multiple transcription factors—including AR, β-catenin, Gli2, HIF1α, STAT3, and p53—by demethylating H3K9me3 at their target promoters, while also antagonizing p53 transcriptional activity through a demethylase-independent mechanism that blocks p53 promoter recruitment [PMID:17555712, PMID:30472235, PMID:32094404, PMID:32754284]. KDM4D protein stability is regulated by TRIM14-recruited deubiquitinases USP14 and BRCC3, which remove K63-linked ubiquitin chains to prevent OPTN-mediated autophagic degradation, and its activity is further modulated by SET7/9-mediated methylation at K427 [PMID:35145029, PMID:38045004].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that KDM4D functions as a transcriptional coactivator resolved how this demethylase connects to gene regulation: it physically associates with ligand-bound androgen receptor and stimulates AR-dependent transcription in a catalytic-activity-dependent manner.\",\n      \"evidence\": \"Co-immunoprecipitation with domain mapping and luciferase reporter assays with catalytic mutants in cell lines\",\n      \"pmids\": [\"17555712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether coactivation extends to other nuclear receptors beyond AR\", \"Genome-wide target identification not performed\", \"Structural basis of the AR–KDM4D interaction undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating KDM4D interaction with p53 and coactivation of p21 expanded its coactivator repertoire beyond nuclear receptors to tumor suppressors and established dual substrate specificity for H3K9me3/me2 and H1.4K26.\",\n      \"evidence\": \"In vitro pulldown, co-immunoprecipitation, and luciferase reporter assays with catalytic mutants\",\n      \"pmids\": [\"22514644\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KDM4D–p53 interaction is activating or inhibitory in vivo remained unresolved until later work\", \"H1.4K26 demethylation relevance in endogenous chromatin not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovering that KDM4D is rapidly recruited to DNA damage sites via PARP1-mediated ADP-ribosylation and is required for ATM activation, Rad51/53BP1 foci, and both HR and NHEJ revealed a non-transcriptional chromatin-modifying role in the DNA damage response.\",\n      \"evidence\": \"Live-cell laser microirradiation imaging, co-immunoprecipitation, siRNA knockdown with DR-GFP and EJ5 repair assays\",\n      \"pmids\": [\"24550317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether demethylase activity is required at damage sites or whether the role is structural\", \"Identity of specific H3K9me3-marked loci altered at damage sites unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying two non-canonical RNA-binding domains in KDM4D and showing that N-terminal RNA binding is required for chromatin association established RNA interaction as a prerequisite for KDM4D's epigenetic function.\",\n      \"evidence\": \"RNA-binding assays, domain-deletion mapping, chromatin fractionation, and H3K9me3 immunofluorescence\",\n      \"pmids\": [\"25378304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of specific RNA species that recruit KDM4D to chromatin unknown\", \"Whether RNA binding is locus-specific or generic not determined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that KDM4D directly binds poly(ADP-ribose) via its C-terminal region linked the RNA-binding and DNA-damage-recruitment functions, explaining how PARP1 activity recruits KDM4D to break sites.\",\n      \"evidence\": \"In vitro PAR binding assay and live-cell imaging at laser-induced damage sites with RNA-binding domain mutants\",\n      \"pmids\": [\"25714495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PAR binding and RNA binding compete for the same C-terminal surface not resolved\", \"In vivo PAR-binding confirmation lacking\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placing KDM4D at DNA replication origins downstream of ORC/MCM but upstream of Cdc45/PCNA loading revealed a replication-licensing function, demonstrating that H3K9me3 removal is a prerequisite for pre-initiation complex assembly.\",\n      \"evidence\": \"siRNA knockdown, H3K9M rescue epistasis, co-immunoprecipitation with replication proteins, and ChIP at origins\",\n      \"pmids\": [\"27679476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KDM4D is selectively targeted to active origins versus silent ones\", \"Whether this role is cell-cycle-phase restricted\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Multiple studies converged to show KDM4D acts as a coactivator for β-catenin/Wnt and HIF1 pathways by demethylating H3K9me3 at target promoters, establishing it as a broad oncogenic transcriptional coactivator in solid tumors.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, promoter-luciferase assays, Kdm4d KO mouse models (colorectal cancer), and tumor xenografts\",\n      \"pmids\": [\"30472235\", \"30060750\", \"32989255\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KDM4D recruitment to Wnt versus HIF targets involves distinct adaptor proteins\", \"Relative contribution of demethylase-dependent versus -independent activities in tumors\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovering that KDM4D inhibits p53 recruitment to target promoters independently of its demethylase activity resolved the earlier paradox of KDM4D both coactivating and antagonizing p53, revealing a dual mechanism with opposing transcriptional outcomes.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, EMSA, and Kdm4d KO mouse DEN-induced liver cancer model\",\n      \"pmids\": [\"32754284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for demethylase-independent p53 sequestration not determined\", \"Whether this mechanism operates in non-hepatic tissues\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of KDM4D interactions with Gli2 (Hedgehog) and Notch1-ICD/β-catenin-TCF4 further broadened the signaling pathways coactivated by KDM4D, linking it to intestinal regeneration and cancer stem cell self-renewal.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, Kdm4d KO mouse colitis model, shRNA knockdown with xenograft\",\n      \"pmids\": [\"32094404\", \"33434575\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether KDM4D binds Gli2 and Notch1-ICD simultaneously or in a mutually exclusive manner\", \"No genome-wide binding profile under Hedgehog/Notch stimulation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Crystal structures of KDM4D with active-site inhibitors at 2.0 Å resolution revealed a ligand-induced loop movement that occludes the histone-binding channel, providing a structural framework for selective inhibitor design.\",\n      \"evidence\": \"X-ray crystallography at 2.0 Å resolution with two distinct inhibitor scaffolds\",\n      \"pmids\": [\"33780862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure with histone peptide substrate for comparison\", \"In vivo efficacy of these inhibitors not reported\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Elucidation of the TRIM14–USP14/BRCC3 deubiquitination axis that prevents K63-linked ubiquitin-mediated autophagic degradation of KDM4D by OPTN revealed how KDM4D protein stability is regulated post-translationally to sustain proinflammatory cytokine production.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assays, autophagy flux assays, and dendritic cell-specific KO models\",\n      \"pmids\": [\"35145029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which E3 ligase attaches the K63-linked chains to KDM4D not identified\", \"Whether this regulatory axis operates outside dendritic cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery of SET7/9-mediated methylation of KDM4D at K427 that modulates its oncogenic activity added a non-histone methylation regulatory layer, showing that KDM4D is itself a methylation substrate with functional consequences.\",\n      \"evidence\": \"In vitro methylation assay, K427R mutagenesis, cell invasion and tumor growth assays, transcriptomics\",\n      \"pmids\": [\"38045004\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How K427 methylation affects demethylase catalytic activity or protein interactions is mechanistically unclear\", \"No structural basis for K427 methylation effect\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing KDM4D pre-associates with enhancer regions and dynamically redistributes to inducible promoters upon innate immune stimulation to demethylate H3K9me2 and drive enhancer RNA transcription established a role in type I interferon responses.\",\n      \"evidence\": \"ChIP-seq, RNA-seq, knockdown/overexpression in MEFs, viral susceptibility assay\",\n      \"pmids\": [\"37275914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the signal that triggers KDM4D redistribution from enhancers to promoters\", \"Whether this enhancer-priming role extends to other innate immune stimuli beyond IFN\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that Kdm4d KO male mice have impaired sperm motility and altered H3K9me3 distribution in round spermatids established a physiological requirement for KDM4D in male fertility beyond its oncological context.\",\n      \"evidence\": \"Kdm4d KO mouse, sperm motility assay, H3K9me3 immunofluorescence in spermatids\",\n      \"pmids\": [\"39034148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific genomic loci where H3K9me3 is aberrantly retained in KO spermatids not mapped\", \"Whether the fertility defect is cell-autonomous in germ cells\", \"Single lab, not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of RNA species that recruit KDM4D to specific chromatin loci, the E3 ubiquitin ligase responsible for K63-linked ubiquitination of KDM4D, the structural basis for its demethylase-independent p53-antagonist function, and whether its diverse coactivator interactions are competitive or combinatorial at individual promoters.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide binding analysis under multiple simultaneous signaling inputs\", \"Structural basis of KDM4D–transcription factor interfaces unresolved\", \"In vivo relevance of H3K79me3 demethylation activity not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 5, 7, 8, 9, 10, 11, 12, 14, 15, 16, 24, 26, 27, 28]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 6, 7, 9, 27]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 7, 10, 11, 13, 20]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [1, 5, 7, 10, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 7, 10, 24]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 5, 24, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0073894\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 7, 10, 11, 20, 24]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 5, 7, 9, 10, 14, 24, 26]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 9, 10, 11, 20, 27]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 23, 24]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 10, 12, 13, 16, 17, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AR\",\n      \"TP53\",\n      \"CTNNB1\",\n      \"GLI2\",\n      \"PARP1\",\n      \"STAT3\",\n      \"TRIM14\",\n      \"HIF1A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}