{"gene":"KDM4D","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2007,"finding":"KDM4D (JMJD2D) forms a complex with ligand-bound androgen receptor (AR) via its C-terminus, and overexpression of KDM4D stimulates AR transcriptional function in a catalytic activity-dependent manner, identifying it as an AR coactivator.","method":"Co-immunoprecipitation, domain mapping, luciferase reporter assay, overexpression/knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and functional reporter assay, single lab, multiple orthogonal methods","pmids":["17555712"],"is_preprint":false},{"year":2012,"finding":"KDM4D (JMJD2D) forms a complex with p53 tumor suppressor, interacting with p53's DNA binding domain, and synergistically activates p21 promoter-driven transcription in a catalytic activity-dependent manner.","method":"Co-immunoprecipitation, in vitro binding assay, luciferase reporter assay, overexpression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro binding plus reporter assay, single lab, 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 damage, and KDM4D is required for efficient ATM substrate phosphorylation, chromatin association of ATM, Rad51 and 53BP1 foci formation, and integrity of homology-directed repair and NHEJ.","method":"Live-cell imaging at laser-induced DNA damage sites, PARP1 inhibition, siRNA knockdown, immunofluorescence, DSB repair assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, ADP-ribosylation, epistasis, DSB repair assays) in a single rigorous study with well-defined mechanistic chain","pmids":["24550317"],"is_preprint":false},{"year":2014,"finding":"KDM4D binds RNA independently of its demethylase activity via two non-canonical RNA binding domains (N-terminal aa 115–236 and C-terminal aa 348–523); RNA interaction with the N-terminal region is required for KDM4D chromatin association and subsequent H3K9me3 demethylation in cells.","method":"RNA binding assays, domain mapping, chromatin fractionation, H3K9me3 immunofluorescence upon RNA binding domain mutations","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping with mutagenesis, chromatin fractionation, and functional H3K9me3 readout, multiple orthogonal methods in one study","pmids":["25378304"],"is_preprint":false},{"year":2015,"finding":"KDM4D binds poly(ADP-ribose) (PAR) in vitro via its C-terminal region, and KDM4D-RNA interaction is required for KDM4D accumulation at DNA breakage sites.","method":"PAR binding assay in vitro, laser micro-irradiation/live-cell imaging with RNA-binding domain mutants","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro PAR binding plus live-cell localization assay with mutants, single lab follow-up of prior PNAS study","pmids":["25714495"],"is_preprint":false},{"year":2016,"finding":"KDM4D regulates DNA replication by reducing H3K9me3 at replication origins; it interacts with replication proteins ORC and MCM (pre-RC components) and its depletion impairs recruitment of Cdc45, PCNA, and polymerase δ (but not ORC/MCM) to origins, blocking pre-initiation complex formation.","method":"siRNA knockdown, chromatin immunoprecipitation, co-immunoprecipitation, rescue with H3K9M histone mutant, DNA replication assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, genetic rescue with H3K9M mutant, replication assays) establishing mechanistic pathway in one rigorous study","pmids":["27679476"],"is_preprint":false},{"year":2017,"finding":"Chemical synthesis of trimethylated H3K79 enabled identification of KDM4D as a potential demethylase of H3K79me3 in vitro, extending its known substrate repertoire beyond H3K9.","method":"Total chemical protein synthesis of H3K79me3, in vitro demethylase assay","journal":"Bioorganic & medicinal chemistry","confidence":"Low","confidence_rationale":"Tier 1 / Weak — in vitro assay only, single lab, described as 'potential' regulator with no cellular validation","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), activating their transcription and promoting colorectal cancer cell proliferation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, shRNA knockdown, xenograft mouse model, Apcmin/+ and JMJD2D-KO mouse crosses","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, reporter assay, multiple genetic mouse models (KO, Apcmin/+), replicated across multiple CRC cell lines","pmids":["30472235"],"is_preprint":false},{"year":2018,"finding":"KDM4D transcriptionally activates HIF1β expression by demethylating H3K9me3 and H3K36me3 at the HIF1β promoter, thereby promoting VEGFA-driven tumor angiogenesis and GIST progression.","method":"ChIP assay, luciferase reporter assay, Co-IP, shRNA knockdown, xenograft model","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, reporter assay, and Co-IP in one study, single lab","pmids":["30060750"],"is_preprint":false},{"year":2018,"finding":"KDM4D promotes TLR4 transcription in hepatic stellate cells by catalyzing H3K9 di- and tri-demethylation at the TLR4 promoter, activating TLR4/NF-κB signaling and contributing to liver fibrogenesis.","method":"ChIP assay, shRNA knockdown, transcriptome analysis, CCl4 mouse model, primary HSC culture","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional knockdown phenotype and in vivo mouse model, single lab","pmids":["30527625"],"is_preprint":false},{"year":2020,"finding":"KDM4D (JMJD2D) promotes Hedgehog target gene expression by interacting with Gli2 and reducing H3K9me3 levels at Hedgehog target gene promoters.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, shRNA knockdown, DSS colitis mouse model, JMJD2D-KO mice","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with KO mouse model validation, single lab","pmids":["32094404"],"is_preprint":false},{"year":2020,"finding":"KDM4D activates HIF1 signaling through three demethylase-activity-dependent mechanisms: (1) cooperating with SOX9 to enhance mTOR expression and promote HIF1α translation; (2) cooperating with c-Fos to enhance HIF1β transcription; (3) interacting and cooperating with HIF1α to enhance glycolytic gene expression.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, overexpression of demethylase-dead mutant, rescue experiments, xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs, catalytic dead mutant validation, functional rescue, single lab","pmids":["32989255"],"is_preprint":false},{"year":2020,"finding":"KDM4D (JMJD2D) directly interacts with p53 and inhibits p53 recruitment to the p21 and PUMA promoters in a demethylation activity-independent manner, antagonizing p53 tumor suppressor function in liver cancer cells.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, electrophoretic mobility shift assay (EMSA), shRNA knockdown, DEN-induced liver cancer mouse model in KO mice","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP, EMSA, and in vivo KO mouse model with multiple orthogonal methods establishing demethylase-independent mechanism","pmids":["32754284"],"is_preprint":false},{"year":2020,"finding":"KDM4D promotes liver cancer stem-like cell self-renewal by reducing H3K9me3 at EpCAM and Sox9 promoters via interaction with β-catenin/TCF4 and Notch1 intracellular domain (NICD), respectively.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, sphere formation assay, xenograft and lung metastasis models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, functional rescue, in vivo models, single lab","pmids":["33434575"],"is_preprint":false},{"year":2020,"finding":"KDM4D cooperates with NFIB and MLL1 complex to regulate adipogenesis; KDM4D demethylation of H3K9me3 is required for NFIB and MLL1 to deposit H3K4me3 and activate PPARγ and C/EBPα expression at bivalent chromatin domains, but KDM4D is dispensable for NFIB/MLL1 binding to target promoters.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, overexpression rescue, adipogenic differentiation assay in C3H10T1/2 cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, genetic rescue experiments, single lab with multiple orthogonal methods","pmids":["32080306"],"is_preprint":false},{"year":2021,"finding":"TRIM14 recruits deubiquitinases USP14 and BRCC3 to cleave K63-linked ubiquitin chains on KDM4D, preventing optineurin (OPTN)-mediated selective autophagic degradation of KDM4D, thereby maintaining KDM4D protein levels and H3K9me3 demethylation to regulate proinflammatory cytokine (IL-12, IL-23) expression in dendritic cells.","method":"Co-immunoprecipitation, ubiquitination assay, autophagy inhibition/induction experiments, TRIM14-KO and KDM4D-KO dendritic cell studies, mouse autoimmune inflammation model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, multiple KO mouse models, epistasis experiments placing KDM4D downstream of TRIM14/USP14/BRCC3 axis","pmids":["35145029"],"is_preprint":false},{"year":2021,"finding":"KDM4D transcriptionally activates SYVN1 expression via H3K9me3 demethylation at the SYVN1 promoter; elevated SYVN1 then mediates ubiquitin-dependent proteasomal degradation of HMGB1, suppressing esophageal squamous cell carcinoma progression.","method":"ChIP assay, in vitro ubiquitination assay, shRNA knockdown, xenograft model","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, in vitro ubiquitination assay, functional rescue, single lab","pmids":["34820329"],"is_preprint":false},{"year":2021,"finding":"KDM4D regulates MCL-1 expression in AML cells by demethylating H3K9me3 at the MCL-1 promoter region.","method":"ChIP assay, shRNA knockdown, cell proliferation and apoptosis assays","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single ChIP assay with knockdown phenotype, single lab, limited mechanistic follow-up","pmids":["34017391"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of KDM4D in complex with two inhibitors (OWS and 10r) at 2.0 Å resolution define the active site binding mode and critical pharmacophores, including unique interactions not previously observed.","method":"X-ray crystallography","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures at 2.0 Å resolution, two independent inhibitor complexes determined","pmids":["33780862"],"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 of the STAT3-IRF1 axis to enhance PD-L1 transcription in a demethylation activity-dependent manner, promoting colorectal cancer immune escape.","method":"Co-immunoprecipitation, ChIP, JMJD2D genetic ablation, tumor infiltrating lymphocyte analysis, xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, catalytic activity dependence, in vivo tumor model, 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 CBLC and PLAGL1, identifying SET7/9 as a writer for KDM4D and K427 methylation as a pro-tumorigenic modification.","method":"In vitro methylation assay, site-directed mutagenesis (K427R), cell growth/invasion assays, xenograft model, transcriptomics","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro methylation assay with mutagenesis and functional consequences in cells and xenograft, single lab","pmids":["38045004"],"is_preprint":false},{"year":2023,"finding":"KDM4D (JMJD2D) stabilizes HBx protein by suppressing TRIM14-mediated ubiquitin-proteasome degradation of HBx, and co-occupies HBV cccDNA with HBx as a coactivator to augment HBV cccDNA transcription and replication.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP on cccDNA, shRNA knockdown, JMJD2D-KO mouse HBV model","journal":"JHEP reports : innovation in hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP on cccDNA, KO mouse model, single lab","pmids":["37701334"],"is_preprint":false},{"year":2023,"finding":"KDM4D suppresses IAV infection by removing H3K9me3 at the RIG-I promoter and cooperating with NF-κB to enhance RIG-I expression, thus boosting innate antiviral signaling.","method":"ChIP assay, shRNA knockdown, KDM4D-KO mouse IAV infection model, Co-immunoprecipitation","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, KO mouse model with defined mechanistic link to RIG-I, single lab","pmids":["42072725"],"is_preprint":false},{"year":2023,"finding":"KDM4D interacts with RPS5 and promotes osteo/dentinogenic differentiation of SCAPs; knockdown of KDM4D increases H3K9me2 and H3K9me3 levels at the CNR1 promoter.","method":"Co-immunoprecipitation, ChIP, RNA microarray, shRNA knockdown, alizarin red staining, scratch migration assay","journal":"Oral diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP and ChIP, single lab, limited mechanistic follow-up on the KDM4D-RPS5 interaction","pmids":["36579641"],"is_preprint":false},{"year":2024,"finding":"KDM4D forms a complex with RPS5 that epigenetically activates CNR1 by demethylating H3K9me2 at its promoter; this enhances mitochondrial membrane potential and energy metabolism to promote osteo/dentinogenic differentiation of DPSCs.","method":"Co-immunoprecipitation, ChIP, mitochondrial functional assays (Seahorse, JC-10, TEM), KDM4D/RPS5 overexpression, subcutaneous transplantation in nude mice","journal":"International endodontic journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, multiple functional readouts including mitochondrial assays and in vivo model, single lab","pmids":["41546606"],"is_preprint":false},{"year":2024,"finding":"Under iron-deficient conditions, KDM4D H3K9me3 demethylase activity is reduced, leading to increased H3K9me3 at the PIK3R3 promoter, suppressed PIK3R3 expression, and inhibition of the PI3K-Akt-Foxo1 pathway, thereby blocking quiescent MSC activation.","method":"ChIP assay, iron chelation/supplementation, shRNA knockdown, Akt pathway inhibition/rescue, iron-deficient mouse model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, pathway rescue experiments, iron-deficient mouse model, single lab","pmids":["39158700"],"is_preprint":false},{"year":2024,"finding":"X-ray crystallographic mapping of the KDM4D histone-binding pocket with novel tetrazole and pyridine core compounds at high resolution revealed interactions with distal residues in the histone-binding site and a loop movement that blocks accessibility to the histone-binding site upon ligand binding.","method":"X-ray crystallography, structure-based drug design","journal":"European journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — X-ray crystallographic structures with multiple compounds revealing conformational details, single lab","pmids":["38981336"],"is_preprint":false},{"year":2024,"finding":"KDM4D cooperates with STAT3 to induce IL-17F expression in colonic epithelial cells by being recruited to the IL-17F promoter and demethylating H3K9me3; JMJD2D also promotes STAT3 phosphorylation.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, JMJD2D-KO mouse C. rodentium infection model","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, KO mouse infection model, single lab","pmids":["38905308"],"is_preprint":false},{"year":2024,"finding":"Kdm4d mutant male mice are subfertile due to impaired sperm motility; absence of Kdm4d is associated with altered H3K9me3 distribution in round spermatids, indicating Kdm4d-mediated H3K9me3 adjustment is required for generation of motile sperm.","method":"Kdm4d knockout mouse generation, sperm motility assay, H3K9me3 immunofluorescence in spermatids, fertilization assays","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific sperm phenotype and H3K9me3 localization readout, single lab","pmids":["39034148"],"is_preprint":false},{"year":2023,"finding":"KDM4D H3K9me2/3 demethylase activity in type I interferon responses: Kdm4d/JMJD2d is associated with enhancer regions genome-wide prior to stimulation and is redistributed to inducible promoters upon activation; depletion attenuates IFN transcriptional response and increases viral susceptibility, while overexpression enhances IFN activation by promoting enhancer RNA transcription and dynamic H3K9me2 demethylation at associated promoters.","method":"Knockdown and overexpression in MEFs, epigenomic analyses (ChIP-seq, eRNA assays), viral infection assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus functional viral susceptibility assays, multiple orthogonal methods, single lab","pmids":["37275914"],"is_preprint":false},{"year":2025,"finding":"USP14 deubiquitinase maintains KDM4D protein levels in airway dendritic cells by preventing its ubiquitination-mediated degradation; reduced KDM4D leads to hypermethylation of the Il10 promoter and impaired immune tolerogenic capacity of dendritic cells.","method":"ChIP assay, KDM4D-KO DC mouse model, ubiquitination analysis, recombinant USP14 treatment, airway allergy mouse model","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, KO mouse model, ubiquitination assay, single lab","pmids":["40088847"],"is_preprint":false}],"current_model":"KDM4D (JMJD2D) is a JmjC-domain histone demethylase that removes di- and tri-methyl marks from H3K9 (and possibly H3K79me3) to activate transcription; its chromatin association requires RNA binding via two non-canonical RNA-binding domains; it is recruited to DNA damage sites via PARP1-mediated ADP-ribosylation and PAR binding through its C-terminal region to facilitate DSB repair; it acts as a coactivator for multiple transcription factors (AR, β-catenin, Gli2, HIF1α, STAT3-IRF1, SP-1, NF-κB) and as a p53 antagonist (in a demethylase-independent manner); its protein stability is regulated by K63-linked ubiquitination (counteracted by USP14/BRCC3 recruited by TRIM14) and autophagic degradation via OPTN, while its activity is modulated by SET7/9-mediated K427 methylation; KDM4D also facilitates pre-initiation complex assembly at DNA replication origins by reducing H3K9me3, and KDM4D-deficient male mice are subfertile due to impaired sperm motility associated with altered H3K9me3 distribution in round spermatids."},"narrative":{"mechanistic_narrative":"KDM4D (JMJD2D) is a JmjC-domain histone demethylase that primarily removes di- and tri-methyl marks from H3K9 to establish a transcriptionally permissive chromatin state at target loci, functioning broadly as a transcriptional coactivator across development, immunity, DNA repair, and cancer [PMID:25378304, PMID:30472235]. Its stable chromatin association is gated by RNA: two non-canonical RNA-binding domains, with the N-terminal region (aa 115–236) required for chromatin association and subsequent H3K9me3 demethylation in cells [PMID:25378304]. In addition to histone catalysis, KDM4D is recruited rapidly to DNA double-strand breaks through its C-terminal region in a PARP1-dependent manner, where it is ADP-ribosylated, binds poly(ADP-ribose), and is required for ATM-dependent signaling and Rad51/53BP1 focus formation during homology-directed repair and NHEJ [PMID:24550317, PMID:25714495]. It also reduces H3K9me3 at replication origins, interacting with pre-RC components ORC and MCM and enabling Cdc45, PCNA, and polymerase δ recruitment to license pre-initiation complex assembly [PMID:27679476]. As a coactivator KDM4D partners with numerous transcription factors—β-catenin/TCF4 and Notch (NICD), Gli2, HIF1α/HIF1β, STAT3-IRF1 and SP-1, NFIB/MLL1, and NF-κB—to demethylate H3K9me3 at their target promoters and drive programs in colorectal and liver cancer, angiogenesis, adipogenesis, and antiviral/innate immune signaling [PMID:30472235, PMID:32094404, PMID:32989255, PMID:32080306, PMID:35027670, PMID:42072725]. Conversely, it antagonizes p53 in a demethylase-independent manner by blocking p53 recruitment to the p21 and PUMA promoters [PMID:32754284]. KDM4D protein abundance is set by a ubiquitin-autophagy axis: TRIM14 recruits the deubiquitinases USP14 and BRCC3 to cleave K63-linked ubiquitin chains and prevent OPTN-mediated selective autophagic degradation, while SET7/9 methylates KDM4D at K427 to potentiate tumorigenesis [PMID:35145029, PMID:38045004, PMID:40088847]. Genetically, Kdm4d-deficient male mice are subfertile owing to impaired sperm motility linked to altered H3K9me3 distribution in round spermatids [PMID:39034148].","teleology":[{"year":2007,"claim":"Established KDM4D as a catalytically dependent transcriptional coactivator by linking it to a nuclear receptor, defining its activating role on chromatin.","evidence":"Co-IP, domain mapping, and luciferase reporter assays with ligand-bound androgen receptor","pmids":["17555712"],"confidence":"Medium","gaps":["No genome-wide AR target validation","Did not resolve which H3K9 methyl state is removed at AR loci"]},{"year":2012,"claim":"Showed KDM4D physically engages the p53 DNA-binding domain and can synergize at the p21 promoter, opening the question of whether KDM4D is a p53 activator or antagonist.","evidence":"Co-IP, in vitro binding, and luciferase reporter assays in overexpression","pmids":["22514644"],"confidence":"Medium","gaps":["Catalytic-dependence vs independence of the p53 effect unresolved here","Overexpression-based; physiological context not tested"]},{"year":2014,"claim":"Defined a chromatin-independent DNA-repair function, placing KDM4D in the PARP1-ADP-ribosylation damage-response pathway upstream of ATM activation and repair focus formation.","evidence":"Live-cell imaging at laser-induced breaks, PARP1 inhibition, siRNA, immunofluorescence, DSB repair assays","pmids":["24550317"],"confidence":"High","gaps":["Whether demethylase activity is needed at break sites not fully separated","Direct ADP-ribose acceptor residues not mapped"]},{"year":2014,"claim":"Revealed that RNA binding via two non-canonical domains is a prerequisite for KDM4D chromatin association, redefining how the enzyme is targeted to substrate.","evidence":"RNA-binding assays, domain mapping with mutagenesis, chromatin fractionation, H3K9me3 immunofluorescence","pmids":["25378304"],"confidence":"High","gaps":["Identity of the bound RNA(s) not determined","Structural basis of non-canonical RNA recognition unknown"]},{"year":2015,"claim":"Connected the RNA-binding requirement to damage recruitment by showing PAR binding through the C-terminus and RNA dependence for accumulation at breaks.","evidence":"In vitro PAR-binding assay and laser micro-irradiation with RNA-binding-domain mutants","pmids":["25714495"],"confidence":"Medium","gaps":["In vitro PAR binding not validated as direct in cells","Single-lab follow-up of the prior study"]},{"year":2016,"claim":"Extended KDM4D function to DNA replication, showing H3K9me3 removal at origins licenses pre-initiation complex assembly downstream of ORC/MCM.","evidence":"siRNA, ChIP, Co-IP, H3K9M histone-mutant rescue, replication assays","pmids":["27679476"],"confidence":"High","gaps":["How KDM4D is recruited to specific origins not defined","Cell-cycle timing of activity not resolved"]},{"year":2017,"claim":"Tested the substrate boundary of KDM4D, raising H3K79me3 as a possible additional substrate beyond H3K9.","evidence":"Total chemical synthesis of H3K79me3 and in vitro demethylase assay","pmids":["28434780"],"confidence":"Low","gaps":["In vitro only with no cellular validation","Described as 'potential' activity"]},{"year":2018,"claim":"Defined KDM4D as a coactivator for oncogenic transcription factors (β-catenin, HIF1β, NF-κB) that demethylates H3K9me3 at their targets to drive cancer and fibrogenic programs.","evidence":"Co-IP, ChIP, reporter assays, shRNA, xenograft and genetic mouse models across CRC, GIST, and liver fibrosis","pmids":["30472235","30060750","30527625"],"confidence":"High","gaps":["Whether factor recruitment depends on KDM4D or vice versa varies by context","Direct vs indirect promoter targeting not always separated"]},{"year":2020,"claim":"Distinguished catalytic from non-catalytic functions, establishing KDM4D as a demethylase-independent p53 antagonist while also coactivating Gli2, HIF1, and β-catenin/Notch-driven stemness.","evidence":"Co-IP, ChIP, EMSA, catalytic-dead mutants, and KO mouse cancer models","pmids":["32754284","32094404","32989255","33434575","32080306"],"confidence":"High","gaps":["Structural basis for p53-recruitment blockade not defined","How catalytic vs non-catalytic modes are selected at different loci unclear"]},{"year":2021,"claim":"Identified the post-translational control of KDM4D abundance, defining a TRIM14–USP14/BRCC3 deubiquitination axis that protects it from OPTN-mediated autophagy and a SET7/9 K427-methylation mark, plus its first crystal structures.","evidence":"Co-IP, ubiquitination assays, autophagy modulation, KO dendritic-cell and inflammation models, in vitro methylation, X-ray crystallography","pmids":["35145029","38045004","33780862","34820329","34017391"],"confidence":"High","gaps":["Ubiquitin ligase placing the K63 chains not identified","How K427 methylation alters catalysis or interactions mechanistically unresolved"]},{"year":2023,"claim":"Broadened KDM4D into innate immunity and interferon biology, showing enhancer-associated localization, redistribution to inducible promoters, and cooperation with NF-κB/STAT3 to boost antiviral genes.","evidence":"ChIP-seq, eRNA assays, knockdown/overexpression in MEFs, Co-IP, and KO mouse viral infection models","pmids":["37275914","42072725","37701334"],"confidence":"Medium","gaps":["How KDM4D enhancer pre-positioning is established not defined","Context-specific antiviral vs proviral (HBx-stabilizing) roles not reconciled"]},{"year":2024,"claim":"Demonstrated physiological and metabolic roles of KDM4D demethylase activity, including iron-sensitive control of stem-cell activation, RPS5-coupled differentiation, STAT3-IL-17F immunity, and a genetic requirement for sperm motility.","evidence":"ChIP, pathway rescue, mitochondrial assays, KO mouse models (infection, fertility), and structural drug-design crystallography","pmids":["39158700","41546606","38905308","39034148","38981336","40088847"],"confidence":"Medium","gaps":["Mechanism coupling iron status to KDM4D activity not biochemically defined","Stage-specific spermatid targets of KDM4D not identified"]},{"year":null,"claim":"It remains unresolved which specific RNAs target KDM4D to chromatin and how this RNA-gated recruitment integrates with PAR binding, transcription-factor partnering, and the choice between catalytic and demethylase-independent modes at any given locus.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified physiological RNA ligand","No unifying model for locus-specific recruitment","Determinants of catalytic vs non-catalytic engagement unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,7,5,9]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[3,7]},{"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":[0,7,11,19]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7,11,19]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,5,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,22,29,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,12,13]}],"complexes":[],"partners":["TP53","CTNNB1","GLI2","HIF1A","STAT3","TRIM14","PARP1","RPS5"],"other_free_text":[]}},"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 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\"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and functional reporter assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17555712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM4D (JMJD2D) forms a complex with p53 tumor suppressor, interacting with p53's DNA binding domain, and synergistically activates p21 promoter-driven transcription in a catalytic activity-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, luciferase reporter assay, overexpression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro binding plus reporter assay, single lab, 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 damage, and KDM4D is required for efficient ATM substrate phosphorylation, chromatin association of ATM, Rad51 and 53BP1 foci formation, and integrity of homology-directed repair and NHEJ.\",\n      \"method\": \"Live-cell imaging at laser-induced DNA damage sites, PARP1 inhibition, siRNA knockdown, immunofluorescence, DSB repair assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, ADP-ribosylation, epistasis, DSB repair assays) in a single rigorous study with well-defined mechanistic chain\",\n      \"pmids\": [\"24550317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM4D binds RNA independently of its demethylase activity via two non-canonical RNA binding domains (N-terminal aa 115–236 and C-terminal aa 348–523); RNA interaction with the N-terminal region is required for KDM4D chromatin association and subsequent H3K9me3 demethylation in cells.\",\n      \"method\": \"RNA binding assays, domain mapping, chromatin fractionation, H3K9me3 immunofluorescence upon RNA binding domain mutations\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping with mutagenesis, chromatin fractionation, and functional H3K9me3 readout, multiple orthogonal methods in one study\",\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 KDM4D-RNA interaction is required for KDM4D accumulation at DNA breakage sites.\",\n      \"method\": \"PAR binding assay in vitro, laser micro-irradiation/live-cell imaging with RNA-binding domain mutants\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro PAR binding plus live-cell localization assay with mutants, single lab follow-up of prior PNAS study\",\n      \"pmids\": [\"25714495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM4D regulates DNA replication by reducing H3K9me3 at replication origins; it interacts with replication proteins ORC and MCM (pre-RC components) and its depletion impairs recruitment of Cdc45, PCNA, and polymerase δ (but not ORC/MCM) to origins, blocking pre-initiation complex formation.\",\n      \"method\": \"siRNA knockdown, chromatin immunoprecipitation, co-immunoprecipitation, rescue with H3K9M histone mutant, DNA replication assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ChIP, genetic rescue with H3K9M mutant, replication assays) establishing mechanistic pathway in one rigorous study\",\n      \"pmids\": [\"27679476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Chemical synthesis of trimethylated H3K79 enabled identification of KDM4D as a potential demethylase of H3K79me3 in vitro, extending its known substrate repertoire beyond H3K9.\",\n      \"method\": \"Total chemical protein synthesis of H3K79me3, in vitro demethylase assay\",\n      \"journal\": \"Bioorganic & medicinal chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro assay only, single lab, described as 'potential' regulator with no cellular validation\",\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), activating their transcription and promoting colorectal cancer cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, shRNA knockdown, xenograft mouse model, Apcmin/+ and JMJD2D-KO mouse crosses\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, reporter assay, multiple genetic mouse models (KO, Apcmin/+), replicated across multiple CRC cell lines\",\n      \"pmids\": [\"30472235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM4D transcriptionally activates HIF1β expression by demethylating H3K9me3 and H3K36me3 at the HIF1β promoter, thereby promoting VEGFA-driven tumor angiogenesis and GIST progression.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, Co-IP, shRNA knockdown, xenograft model\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, reporter assay, and Co-IP in one study, single lab\",\n      \"pmids\": [\"30060750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM4D promotes TLR4 transcription in hepatic stellate cells by catalyzing H3K9 di- and tri-demethylation at the TLR4 promoter, activating TLR4/NF-κB signaling and contributing to liver fibrogenesis.\",\n      \"method\": \"ChIP assay, shRNA knockdown, transcriptome analysis, CCl4 mouse model, primary HSC culture\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional knockdown phenotype and in vivo mouse model, single lab\",\n      \"pmids\": [\"30527625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4D (JMJD2D) promotes Hedgehog target gene expression by interacting with Gli2 and reducing H3K9me3 levels at Hedgehog target gene promoters.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, shRNA knockdown, DSS colitis mouse model, JMJD2D-KO mice\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with KO mouse model validation, single lab\",\n      \"pmids\": [\"32094404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4D activates HIF1 signaling through three demethylase-activity-dependent mechanisms: (1) cooperating with SOX9 to enhance mTOR expression and promote HIF1α translation; (2) cooperating with c-Fos to enhance HIF1β transcription; (3) interacting and cooperating with HIF1α to enhance glycolytic gene expression.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, overexpression of demethylase-dead mutant, rescue experiments, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs, catalytic dead mutant validation, functional rescue, single lab\",\n      \"pmids\": [\"32989255\"],\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 demethylation activity-independent manner, antagonizing p53 tumor suppressor function in liver cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, electrophoretic mobility shift assay (EMSA), shRNA knockdown, DEN-induced liver cancer mouse model in KO mice\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP, EMSA, and in vivo KO mouse model with multiple orthogonal methods establishing demethylase-independent mechanism\",\n      \"pmids\": [\"32754284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4D promotes liver cancer stem-like cell self-renewal by reducing H3K9me3 at EpCAM and Sox9 promoters via interaction with β-catenin/TCF4 and Notch1 intracellular domain (NICD), respectively.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, sphere formation assay, xenograft and lung metastasis models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, functional rescue, in vivo models, single lab\",\n      \"pmids\": [\"33434575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4D cooperates with NFIB and MLL1 complex to regulate adipogenesis; KDM4D demethylation of H3K9me3 is required for NFIB and MLL1 to deposit H3K4me3 and activate PPARγ and C/EBPα expression at bivalent chromatin domains, but KDM4D is dispensable for NFIB/MLL1 binding to target promoters.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, overexpression rescue, adipogenic differentiation assay in C3H10T1/2 cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, genetic rescue experiments, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32080306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM14 recruits deubiquitinases USP14 and BRCC3 to cleave K63-linked ubiquitin chains on KDM4D, preventing optineurin (OPTN)-mediated selective autophagic degradation of KDM4D, thereby maintaining KDM4D protein levels and H3K9me3 demethylation to regulate proinflammatory cytokine (IL-12, IL-23) expression in dendritic cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, autophagy inhibition/induction experiments, TRIM14-KO and KDM4D-KO dendritic cell studies, mouse autoimmune inflammation model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, multiple KO mouse models, epistasis experiments placing KDM4D downstream of TRIM14/USP14/BRCC3 axis\",\n      \"pmids\": [\"35145029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4D transcriptionally activates SYVN1 expression via H3K9me3 demethylation at the SYVN1 promoter; elevated SYVN1 then mediates ubiquitin-dependent proteasomal degradation of HMGB1, suppressing esophageal squamous cell carcinoma progression.\",\n      \"method\": \"ChIP assay, in vitro ubiquitination assay, shRNA knockdown, xenograft model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, in vitro ubiquitination assay, functional rescue, single lab\",\n      \"pmids\": [\"34820329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4D regulates MCL-1 expression in AML cells by demethylating H3K9me3 at the MCL-1 promoter region.\",\n      \"method\": \"ChIP assay, shRNA knockdown, cell proliferation and apoptosis assays\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single ChIP assay with knockdown phenotype, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"34017391\"],\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 define the active site binding mode and critical pharmacophores, including unique interactions not previously observed.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures at 2.0 Å resolution, two independent inhibitor complexes determined\",\n      \"pmids\": [\"33780862\"],\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 of the STAT3-IRF1 axis to enhance PD-L1 transcription in a demethylation activity-dependent manner, promoting colorectal cancer immune escape.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, JMJD2D genetic ablation, tumor infiltrating lymphocyte analysis, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, catalytic activity dependence, in vivo tumor model, 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 CBLC and PLAGL1, identifying SET7/9 as a writer for KDM4D and K427 methylation as a pro-tumorigenic modification.\",\n      \"method\": \"In vitro methylation assay, site-directed mutagenesis (K427R), cell growth/invasion assays, xenograft model, transcriptomics\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro methylation assay with mutagenesis and functional consequences in cells and xenograft, 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 of HBx, and co-occupies HBV cccDNA with HBx as a coactivator to augment HBV cccDNA transcription and replication.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP on cccDNA, shRNA knockdown, JMJD2D-KO mouse HBV model\",\n      \"journal\": \"JHEP reports : innovation in hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, ChIP on cccDNA, KO mouse model, single lab\",\n      \"pmids\": [\"37701334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM4D suppresses IAV infection by removing H3K9me3 at the RIG-I promoter and cooperating with NF-κB to enhance RIG-I expression, thus boosting innate antiviral signaling.\",\n      \"method\": \"ChIP assay, shRNA knockdown, KDM4D-KO mouse IAV infection model, Co-immunoprecipitation\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, KO mouse model with defined mechanistic link to RIG-I, single lab\",\n      \"pmids\": [\"42072725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM4D interacts with RPS5 and promotes osteo/dentinogenic differentiation of SCAPs; knockdown of KDM4D increases H3K9me2 and H3K9me3 levels at the CNR1 promoter.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, RNA microarray, shRNA knockdown, alizarin red staining, scratch migration assay\",\n      \"journal\": \"Oral diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP and ChIP, single lab, limited mechanistic follow-up on the KDM4D-RPS5 interaction\",\n      \"pmids\": [\"36579641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM4D forms a complex with RPS5 that epigenetically activates CNR1 by demethylating H3K9me2 at its promoter; this enhances mitochondrial membrane potential and energy metabolism to promote osteo/dentinogenic differentiation of DPSCs.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, mitochondrial functional assays (Seahorse, JC-10, TEM), KDM4D/RPS5 overexpression, subcutaneous transplantation in nude mice\",\n      \"journal\": \"International endodontic journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, multiple functional readouts including mitochondrial assays and in vivo model, single lab\",\n      \"pmids\": [\"41546606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under iron-deficient conditions, KDM4D H3K9me3 demethylase activity is reduced, leading to increased H3K9me3 at the PIK3R3 promoter, suppressed PIK3R3 expression, and inhibition of the PI3K-Akt-Foxo1 pathway, thereby blocking quiescent MSC activation.\",\n      \"method\": \"ChIP assay, iron chelation/supplementation, shRNA knockdown, Akt pathway inhibition/rescue, iron-deficient mouse model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, pathway rescue experiments, iron-deficient mouse model, single lab\",\n      \"pmids\": [\"39158700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"X-ray crystallographic mapping of the KDM4D histone-binding pocket with novel tetrazole and pyridine core compounds at high resolution revealed interactions with distal residues in the histone-binding site and a loop movement that blocks accessibility to the histone-binding site upon ligand binding.\",\n      \"method\": \"X-ray crystallography, structure-based drug design\",\n      \"journal\": \"European journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — X-ray crystallographic structures with multiple compounds revealing conformational details, single lab\",\n      \"pmids\": [\"38981336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM4D cooperates with STAT3 to induce IL-17F expression in colonic epithelial cells by being recruited to the IL-17F promoter and demethylating H3K9me3; JMJD2D also promotes STAT3 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, JMJD2D-KO mouse C. rodentium infection model\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, KO mouse infection model, single lab\",\n      \"pmids\": [\"38905308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Kdm4d mutant male mice are subfertile due to impaired sperm motility; absence of Kdm4d is associated with altered H3K9me3 distribution in round spermatids, indicating Kdm4d-mediated H3K9me3 adjustment is required for generation of motile sperm.\",\n      \"method\": \"Kdm4d knockout mouse generation, sperm motility assay, H3K9me3 immunofluorescence in spermatids, fertilization assays\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific sperm phenotype and H3K9me3 localization readout, single lab\",\n      \"pmids\": [\"39034148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM4D H3K9me2/3 demethylase activity in type I interferon responses: Kdm4d/JMJD2d is associated with enhancer regions genome-wide prior to stimulation and is redistributed to inducible promoters upon activation; depletion attenuates IFN transcriptional response and increases viral susceptibility, while overexpression enhances IFN activation by promoting enhancer RNA transcription and dynamic H3K9me2 demethylation at associated promoters.\",\n      \"method\": \"Knockdown and overexpression in MEFs, epigenomic analyses (ChIP-seq, eRNA assays), viral infection assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus functional viral susceptibility assays, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"37275914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP14 deubiquitinase maintains KDM4D protein levels in airway dendritic cells by preventing its ubiquitination-mediated degradation; reduced KDM4D leads to hypermethylation of the Il10 promoter and impaired immune tolerogenic capacity of dendritic cells.\",\n      \"method\": \"ChIP assay, KDM4D-KO DC mouse model, ubiquitination analysis, recombinant USP14 treatment, airway allergy mouse model\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, KO mouse model, ubiquitination assay, single lab\",\n      \"pmids\": [\"40088847\"],\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 possibly H3K79me3) to activate transcription; its chromatin association requires RNA binding via two non-canonical RNA-binding domains; it is recruited to DNA damage sites via PARP1-mediated ADP-ribosylation and PAR binding through its C-terminal region to facilitate DSB repair; it acts as a coactivator for multiple transcription factors (AR, β-catenin, Gli2, HIF1α, STAT3-IRF1, SP-1, NF-κB) and as a p53 antagonist (in a demethylase-independent manner); its protein stability is regulated by K63-linked ubiquitination (counteracted by USP14/BRCC3 recruited by TRIM14) and autophagic degradation via OPTN, while its activity is modulated by SET7/9-mediated K427 methylation; KDM4D also facilitates pre-initiation complex assembly at DNA replication origins by reducing H3K9me3, and KDM4D-deficient male mice are subfertile due to impaired sperm motility associated with altered H3K9me3 distribution in round spermatids.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM4D (JMJD2D) is a JmjC-domain histone demethylase that primarily removes di- and tri-methyl marks from H3K9 to establish a transcriptionally permissive chromatin state at target loci, functioning broadly as a transcriptional coactivator across development, immunity, DNA repair, and cancer [#3, #7]. Its stable chromatin association is gated by RNA: two non-canonical RNA-binding domains, with the N-terminal region (aa 115\\u2013236) required for chromatin association and subsequent H3K9me3 demethylation in cells [#3]. In addition to histone catalysis, KDM4D is recruited rapidly to DNA double-strand breaks through its C-terminal region in a PARP1-dependent manner, where it is ADP-ribosylated, binds poly(ADP-ribose), and is required for ATM-dependent signaling and Rad51/53BP1 focus formation during homology-directed repair and NHEJ [#2, #4]. It also reduces H3K9me3 at replication origins, interacting with pre-RC components ORC and MCM and enabling Cdc45, PCNA, and polymerase \\u03b4 recruitment to license pre-initiation complex assembly [#5]. As a coactivator KDM4D partners with numerous transcription factors\\u2014\\u03b2-catenin/TCF4 and Notch (NICD), Gli2, HIF1\\u03b1/HIF1\\u03b2, STAT3-IRF1 and SP-1, NFIB/MLL1, and NF-\\u03baB\\u2014to demethylate H3K9me3 at their target promoters and drive programs in colorectal and liver cancer, angiogenesis, adipogenesis, and antiviral/innate immune signaling [#7, #10, #11, #14, #19, #22]. Conversely, it antagonizes p53 in a demethylase-independent manner by blocking p53 recruitment to the p21 and PUMA promoters [#12]. KDM4D protein abundance is set by a ubiquitin-autophagy axis: TRIM14 recruits the deubiquitinases USP14 and BRCC3 to cleave K63-linked ubiquitin chains and prevent OPTN-mediated selective autophagic degradation, while SET7/9 methylates KDM4D at K427 to potentiate tumorigenesis [#15, #20, #30]. Genetically, Kdm4d-deficient male mice are subfertile owing to impaired sperm motility linked to altered H3K9me3 distribution in round spermatids [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established KDM4D as a catalytically dependent transcriptional coactivator by linking it to a nuclear receptor, defining its activating role on chromatin.\",\n      \"evidence\": \"Co-IP, domain mapping, and luciferase reporter assays with ligand-bound androgen receptor\",\n      \"pmids\": [\"17555712\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No genome-wide AR target validation\", \"Did not resolve which H3K9 methyl state is removed at AR loci\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed KDM4D physically engages the p53 DNA-binding domain and can synergize at the p21 promoter, opening the question of whether KDM4D is a p53 activator or antagonist.\",\n      \"evidence\": \"Co-IP, in vitro binding, and luciferase reporter assays in overexpression\",\n      \"pmids\": [\"22514644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic-dependence vs independence of the p53 effect unresolved here\", \"Overexpression-based; physiological context not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a chromatin-independent DNA-repair function, placing KDM4D in the PARP1-ADP-ribosylation damage-response pathway upstream of ATM activation and repair focus formation.\",\n      \"evidence\": \"Live-cell imaging at laser-induced breaks, PARP1 inhibition, siRNA, immunofluorescence, DSB repair assays\",\n      \"pmids\": [\"24550317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether demethylase activity is needed at break sites not fully separated\", \"Direct ADP-ribose acceptor residues not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed that RNA binding via two non-canonical domains is a prerequisite for KDM4D chromatin association, redefining how the enzyme is targeted to substrate.\",\n      \"evidence\": \"RNA-binding assays, domain mapping with mutagenesis, chromatin fractionation, H3K9me3 immunofluorescence\",\n      \"pmids\": [\"25378304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the bound RNA(s) not determined\", \"Structural basis of non-canonical RNA recognition unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected the RNA-binding requirement to damage recruitment by showing PAR binding through the C-terminus and RNA dependence for accumulation at breaks.\",\n      \"evidence\": \"In vitro PAR-binding assay and laser micro-irradiation with RNA-binding-domain mutants\",\n      \"pmids\": [\"25714495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro PAR binding not validated as direct in cells\", \"Single-lab follow-up of the prior study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended KDM4D function to DNA replication, showing H3K9me3 removal at origins licenses pre-initiation complex assembly downstream of ORC/MCM.\",\n      \"evidence\": \"siRNA, ChIP, Co-IP, H3K9M histone-mutant rescue, replication assays\",\n      \"pmids\": [\"27679476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KDM4D is recruited to specific origins not defined\", \"Cell-cycle timing of activity not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Tested the substrate boundary of KDM4D, raising H3K79me3 as a possible additional substrate beyond H3K9.\",\n      \"evidence\": \"Total chemical synthesis of H3K79me3 and in vitro demethylase assay\",\n      \"pmids\": [\"28434780\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"In vitro only with no cellular validation\", \"Described as 'potential' activity\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined KDM4D as a coactivator for oncogenic transcription factors (\\u03b2-catenin, HIF1\\u03b2, NF-\\u03baB) that demethylates H3K9me3 at their targets to drive cancer and fibrogenic programs.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays, shRNA, xenograft and genetic mouse models across CRC, GIST, and liver fibrosis\",\n      \"pmids\": [\"30472235\", \"30060750\", \"30527625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether factor recruitment depends on KDM4D or vice versa varies by context\", \"Direct vs indirect promoter targeting not always separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Distinguished catalytic from non-catalytic functions, establishing KDM4D as a demethylase-independent p53 antagonist while also coactivating Gli2, HIF1, and \\u03b2-catenin/Notch-driven stemness.\",\n      \"evidence\": \"Co-IP, ChIP, EMSA, catalytic-dead mutants, and KO mouse cancer models\",\n      \"pmids\": [\"32754284\", \"32094404\", \"32989255\", \"33434575\", \"32080306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for p53-recruitment blockade not defined\", \"How catalytic vs non-catalytic modes are selected at different loci unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the post-translational control of KDM4D abundance, defining a TRIM14\\u2013USP14/BRCC3 deubiquitination axis that protects it from OPTN-mediated autophagy and a SET7/9 K427-methylation mark, plus its first crystal structures.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, autophagy modulation, KO dendritic-cell and inflammation models, in vitro methylation, X-ray crystallography\",\n      \"pmids\": [\"35145029\", \"38045004\", \"33780862\", \"34820329\", \"34017391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase placing the K63 chains not identified\", \"How K427 methylation alters catalysis or interactions mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened KDM4D into innate immunity and interferon biology, showing enhancer-associated localization, redistribution to inducible promoters, and cooperation with NF-\\u03baB/STAT3 to boost antiviral genes.\",\n      \"evidence\": \"ChIP-seq, eRNA assays, knockdown/overexpression in MEFs, Co-IP, and KO mouse viral infection models\",\n      \"pmids\": [\"37275914\", \"42072725\", \"37701334\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How KDM4D enhancer pre-positioning is established not defined\", \"Context-specific antiviral vs proviral (HBx-stabilizing) roles not reconciled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated physiological and metabolic roles of KDM4D demethylase activity, including iron-sensitive control of stem-cell activation, RPS5-coupled differentiation, STAT3-IL-17F immunity, and a genetic requirement for sperm motility.\",\n      \"evidence\": \"ChIP, pathway rescue, mitochondrial assays, KO mouse models (infection, fertility), and structural drug-design crystallography\",\n      \"pmids\": [\"39158700\", \"41546606\", \"38905308\", \"39034148\", \"38981336\", \"40088847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling iron status to KDM4D activity not biochemically defined\", \"Stage-specific spermatid targets of KDM4D not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which specific RNAs target KDM4D to chromatin and how this RNA-gated recruitment integrates with PAR binding, transcription-factor partnering, and the choice between catalytic and demethylase-independent modes at any given locus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified physiological RNA ligand\", \"No unifying model for locus-specific recruitment\", \"Determinants of catalytic vs non-catalytic engagement unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 7, 5, 9]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 7, 11, 19]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7, 11, 19]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 22, 29, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 12, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TP53\", \"CTNNB1\", \"GLI2\", \"HIF1A\", \"STAT3\", \"TRIM14\", \"PARP1\", \"RPS5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}