{"gene":"KDM4B","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2006,"finding":"Jmjd2b (KDM4B) actively removes H3K9me3 at pericentric heterochromatin in mammalian cells; metabolic labeling with heavy methyl groups demonstrated this is an active demethylation process occurring before DNA replication. Recombinant Jmjd2b appeared as a poor enzyme in vitro, yet also reduced H3K36 methylation.","method":"Inducible Jmjd2b-GFP cell lines, metabolic labeling with heavy methyl groups (SILAC-based), immunofluorescence","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct metabolic labeling demonstrated active H3K9me3 removal in vivo; replicated by multiple labs subsequently","pmids":["16738407"],"is_preprint":false},{"year":2011,"finding":"JMJD2B (KDM4B) is an integral component of the MLL2 H3K4 methyltransferase complex and co-purifies with estrogen receptor α (ERα). H3K9 demethylation by JMJD2B is a prerequisite for H3K4 methylation at ERα target gene promoters, coordinating the mutual exclusivity of H3K9 and H3K4 methylation during ERα-activated transcription.","method":"Affinity purification/co-purification, ChIP, siRNA knockdown, in vitro transcription assays, xenograft tumor assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — complex purification, ChIP, functional knockdown with multiple readouts; replicated by independent labs","pmids":["21502505"],"is_preprint":false},{"year":2011,"finding":"JMJD2B (KDM4B) interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex; it is recruited to ERα target sites where it demethylates H3K9me3 to facilitate transcription of ER-responsive genes including MYB, MYC, and CCND1.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, mammary gland-specific conditional knockout mice","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, in vivo genetic deletion, replicated independently","pmids":["21445275"],"is_preprint":false},{"year":2008,"finding":"HIF-1α directly binds recognition sites in the JMJD2B gene promoter and induces its transcription under hypoxia; ectopically expressed JMJD2B retains histone lysine demethylase activity under hypoxic conditions.","method":"ChIP, reporter assay, qRT-PCR, Western blot, ectopic expression with demethylase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct ChIP of HIF-1α at JMJD2B promoter, functional demethylase activity confirmed in hypoxia; replicated by multiple subsequent studies","pmids":["18984585"],"is_preprint":false},{"year":2013,"finding":"KDM4B enzymatic (demethylase) activity is required to enhance androgen receptor (AR) transcriptional activity; independently of demethylase activity, KDM4B enhances AR protein stability by inhibiting AR ubiquitination. Knockdown of KDM4B causes near-complete depletion of AR protein. KDM4B is itself androgen-regulated.","method":"siRNA screen, co-immunoprecipitation, ubiquitination assay, luciferase reporter, Western blot","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — enzymatic activity mutants tested, ubiquitination assay, multiple cell lines; single lab with orthogonal methods","pmids":["23435229"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of KDM4B in ternary complex with pyridine 2,4-dicarboxylic acid and H3K9me3 peptide was solved, revealing the active-site architecture and a selective K9/K36 binding site. Pharmacological and genetic inhibition of KDM4B increased H3K9me3 and silenced growth-related AR-responsive genes.","method":"X-ray crystallography, virtual screening, in vitro enzymatic inhibition assay, ChIP, cell viability assay","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure solved with functional validation by inhibition and mutagenesis; single lab but multiple orthogonal methods","pmids":["24971742"],"is_preprint":false},{"year":2013,"finding":"KDM4B controls expression of ER and FOXA1 genes by demethylating repressive H3K9me3 marks in their upstream regulatory regions, enabling GATA-3 binding. KDM4B physically interacts with GATA-3 in breast cancer cells and co-activates GATA-3 transcriptional activity.","method":"Co-immunoprecipitation, ChIP, luciferase reporter, siRNA knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with functional reporter assay; single lab","pmids":["23723241"],"is_preprint":false},{"year":2013,"finding":"Kdm4b is rapidly recruited to DNA double-strand breaks induced by laser micro-irradiation in a PARP1-dependent and demethylase-activity-dependent manner. Overexpression of Kdm4b decreased γH2AX foci 6 hours after γ-irradiation and increased cell survival. H3K9me2/3 levels decreased at early time points after γ-irradiation.","method":"Laser micro-irradiation, live-cell imaging (EGFP fusion), PARP inhibitor treatment, γH2AX foci quantification, clonogenic survival assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct live-cell recruitment assay, pharmacological dissection of PARP1 dependency, demethylase-dead mutant used; multiple orthogonal methods in single lab","pmids":["23744078"],"is_preprint":false},{"year":2012,"finding":"KDM4B promotes osteogenic commitment of MSCs by removing repressive H3K9me3 at DLX gene loci, thereby activating DLX expression. KDM6B acts in parallel on H3K27me3/HOX. Depletion of KDM4B shifts MSCs toward adipogenesis.","method":"shRNA knockdown, ChIP, differentiation assays (osteogenic/adipogenic), ovariectomized and aging mouse models","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating H3K9me3 removal at DLX loci, KO phenotype in vivo; replicated in multiple subsequent studies","pmids":["22770241"],"is_preprint":false},{"year":2013,"finding":"Jmjd2b and Jmjd2c (KDM4C) are necessary for self-renewal of mouse ESCs and iPS cell generation. Genome-wide occupancy reveals Jmjd2b-unique target sites belong to the Core (Nanog) regulatory module; Jmjd2b and Nanog act through an interconnected regulatory loop.","method":"RNAi screen, genome-wide ChIP-seq occupancy, iPS reprogramming assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq combined with functional RNAi screen and iPS assays; rigorous study","pmids":["24361252"],"is_preprint":false},{"year":2013,"finding":"Heat shock protein Hsp90 physically interacts with and stabilizes KDM4B protein. Pharmacological Hsp90 inhibition with geldanamycin causes ubiquitin-dependent proteasomal degradation of KDM4B (but not KDM4C). KDM4B is ubiquitinated on lysines 337 and 562; simultaneous K337R/K562R substitution suppresses geldanamycin-induced degradation.","method":"Co-immunoprecipitation, pharmacological inhibition (geldanamycin), ubiquitination assay, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — Co-IP, mutagenesis of ubiquitination sites, pharmacological validation; single lab with multiple orthogonal methods","pmids":["23589305"],"is_preprint":false},{"year":2012,"finding":"Histone demethylase Kdm4b acts as a co-factor of C/EBPβ during mitotic clonal expansion (MCE) of 3T3-L1 preadipocytes. Kdm4b expression is induced by C/EBPβ binding to its promoter; Kdm4b interacts with C/EBPβ, is recruited to promoters of C/EBPβ-regulated cell cycle genes (Cdc45l, Mcm3, Gins1, Cdc25c), demethylates H3K9me3 there, and activates their transcription.","method":"ChIP-on-chip, EMSA, luciferase assay, co-immunoprecipitation, siRNA knockdown, ChIP","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, EMSA, reporter assay); single lab","pmids":["22722334"],"is_preprint":false},{"year":2013,"finding":"p53 directly induces JMJD2B gene expression by binding a canonical p53 consensus motif in the JMJD2B promoter. JMJD2B induction attenuates transcription of p53 targets (p21, PIG3, PUMA) in a catalytic-activity-dependent manner, forming a negative auto-regulatory feedback loop on p53 transcriptional output.","method":"ChIP, siRNA knockdown, luciferase reporter, gain/loss-of-function, xenograft tumor assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP of p53 at JMJD2B promoter, catalytic mutant tested; single lab","pmids":["28073943"],"is_preprint":false},{"year":2013,"finding":"p53 directly induces JMJD2b expression through promoter binding, leading to reduction of H3K9me3 at pericentric heterochromatin after DNA damage. JMJD2b depletion delays slow-phase HC DNA repair and reduces clonogenic survival after ionizing irradiation.","method":"ChIP, siRNA knockdown, IR survival assay, Western blot","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP for p53 at JMJD2b promoter; single lab, complementary to PMID 28073943","pmids":["23376847"],"is_preprint":false},{"year":2015,"finding":"TGF-β induces KDM4B expression in MSCs; KDM4B is recruited to the SOX9 promoter, removes H3K9me3, and activates SOX9 transcription. KDM4B depletion reduces SMAD3 occupancy at the SOX9 promoter, establishing KDM4B as required for SMAD-dependent coactivation of SOX9 during chondrogenesis.","method":"ChIP, shRNA knockdown, overexpression, differentiation assays","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing KDM4B at SOX9 promoter with H3K9me3 removal; single lab","pmids":["26485430"],"is_preprint":false},{"year":2019,"finding":"KDM4B is phosphorylated by protein kinase A (PKA) under castration-resistance–promoting conditions, enabling its binding to splicing factor SF3B3. KDM4B binds RNA near the 5'-CE3 region of AR pre-mRNA, increases chromatin accessibility, and couples the spliceosome to chromatin to promote inclusion of CE3, generating the AR-V7 splice variant.","method":"Immunoprecipitation, RNA immunoprecipitation, ATAC-seq, genome-wide splicing profiling, phosphorylation assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — RIP, phosphorylation mapping, ATAC-seq, multiple orthogonal methods in single lab establishing novel non-histone function","pmids":["31647098"],"is_preprint":false},{"year":2018,"finding":"SCF^Fbxo22 ubiquitylates KDM4B complexed with tamoxifen-bound ERα, leading to KDM4B degradation and release of steroid receptor coactivator (SRC) from ER. This Fbxo22-dependent KDM4B degradation is required for tamoxifen antagonist activity; Fbxo22 depletion restores ER-dependent transcription via AF1 even in SERM-treated cells.","method":"Co-immunoprecipitation, ubiquitination assay, live-cell fluorescence imaging (FRET/BiFC), ChIP, in vitro and in vivo tumor growth","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical ubiquitination assay, live-cell imaging, ChIP on nearly all ER-SRC-bound enhancers, in vivo validation; multiple orthogonal methods","pmids":["30418174"],"is_preprint":false},{"year":2014,"finding":"KDM4B forms complexes with β-catenin in vitro and in vivo (involving KDM4B amino acids 353–740) and also interacts with TCF4. KDM4B co-occupies β-catenin/TCF4 target gene promoters, and its knockdown reduces expression of JUN, MYC, and Cyclin D1.","method":"Co-immunoprecipitation (in vitro and in vivo), ChIP, siRNA knockdown, clonogenic assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vitro and in vivo Co-IP with domain mapping, ChIP; single lab","pmids":["24481461"],"is_preprint":false},{"year":2013,"finding":"JMJD2B physically associates with β-catenin and enhances its nuclear localization and transcriptional activity in gastric cancer cells. JMJD2B binds the vimentin promoter together with β-catenin and induces local H3K9 demethylation to activate vimentin transcription, promoting EMT.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, invasion/migration assays, in vivo metastasis","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with functional EMT readouts; single lab","pmids":["24077348"],"is_preprint":false},{"year":2015,"finding":"In chick embryo, KDM4B dynamically occupies regulatory regions of the Dlx3 locus and removes H3K9me3 to activate Dlx3 expression; loss of KDM4B causes defective otic vesicle invagination. A catalytically dead KDM4B mutant fails to rescue the invagination phenotype, whereas DLX3 co-electroporation rescues it, placing KDM4B upstream of DLX3 in otic placode invagination.","method":"In vivo ChIP, electroporation/knockdown in chick embryo, rescue with catalytic-dead mutant","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vivo ChIP with catalytic dead mutant rescue experiment; single lab but multiple orthogonal methods","pmids":["26598618"],"is_preprint":false},{"year":2021,"finding":"Loss of KDM4B in MSCs increases H3K9me3 and impairs β-catenin/Smad1-mediated transcription. KDM4B ablation induces senescence-associated heterochromatin foci formation and promotes MSC exhaustion. KDM4B is required for parathyroid hormone-mediated bone anabolic signaling.","method":"Conditional knockout mice, ChIP, differentiation assays, senescence assays","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo conditional KO with ChIP and mechanistic pathway dissection; replicated across multiple conditions","pmids":["33571444"],"is_preprint":false},{"year":2021,"finding":"KDM4B physically and functionally associates with CCAR1 and MED1 in a complex. This KDM4B-CCAR1-MED1 complex localizes to promoters of osteoclast-related genes upon RANKL stimulation, induces H3K9 demethylation (euchromatinization), and recruits NF-κB p65 via a direct interaction between KDM4B and p65.","method":"Co-immunoprecipitation, genome-wide ChIP-seq, conditional KO mice (myeloid-specific), in vivo KDM4B inhibitor treatment","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, in vivo genetic and pharmacological validation; single lab with multiple orthogonal methods","pmids":["34031372"],"is_preprint":false},{"year":2021,"finding":"Inactivation of KDM4B (via H3.3G34R or IDH1/2 mutations) cooperates with ATRX loss to drive Alternative Lengthening of Telomeres (ALT) in glioblastoma. KDM4B overexpression in ALT cancer cells abrogates ALT-associated features, identifying KDM4B as the key demethylase whose inactivation promotes ALT.","method":"Mouse ESC genetic KO (ATRX, TP53, TERT, KDM4B), KDM4B overexpression in ALT cells, telomere characterization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic rescue and loss-of-function in multiple models with ALT phenotypic readouts; single lab but rigorous","pmids":["33972520"],"is_preprint":false},{"year":2018,"finding":"KDM4B interacts with eIF2α in the cytoplasm and maintains reduced phosphorylation of eIF2α; this cytoplasmic function is independent of its canonical histone demethylase role but requires demethylase activity. KDM4B depletion or inhibition activates the unfolded protein response (UPR) and causes preferential apoptosis in PTEN-deficient triple-negative breast cancers.","method":"Co-immunoprecipitation (cytoplasmic fraction), siRNA/small molecule inhibition, UPR pathway activation assays, apoptosis assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cytoplasmic Co-IP with eIF2α, demethylase-activity dependence tested; single lab","pmids":["30266800"],"is_preprint":false},{"year":2017,"finding":"KDM4B activates LINE-1 retrotransposons by removing H3K9me3 from evolutionarily young LINE-1 elements genome-wide. KDM4B overexpression enhances LINE-1 retrotransposition efficacy, copy number, and associated DNA damage in breast cancer cells.","method":"Genome-wide H3K9me3 ChIP-seq, LINE-1 retrotransposition assay, copy number analysis, KDM4B inhibitor treatment","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with functional retrotransposition assay; single lab","pmids":["30459150"],"is_preprint":false},{"year":2019,"finding":"N-Myc physically interacts with and recruits KDM4B in neuroblastoma cells. KDM4B regulates Myc pathway target genes and neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo.","method":"Immunoprecipitation, immunofluorescence, ChIP, shRNA knockdown, xenograft","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP showing N-Myc/KDM4B interaction with ChIP; single lab","pmids":["25925418"],"is_preprint":false},{"year":2017,"finding":"JMJD2B activity controls autophagy via epigenetic regulation of LC3B (MAP1LC3B) gene expression; JMJD2B knockdown reduces H3K9 demethylation at the LC3B promoter and decreases autophagy, reducing intracellular amino acid availability under glucose deprivation in colorectal cancer cells.","method":"ChIP, siRNA knockdown, metabolic profiling, xenograft, immunofluorescence, electron microscopy","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at LC3B promoter with multiple metabolic and functional assays; single lab","pmids":["32483417"],"is_preprint":false},{"year":2019,"finding":"KDM4B physically interacts with c-Jun and co-occupies the IL-8, MMP1, and ITGAV promoters; demethylase activity is required for KDM4B-mediated upregulation of these targets. KDM4B depletion reduces integrin αV expression and impairs H. pylori-induced cell migration.","method":"Co-immunoprecipitation, ChIP, demethylase-dead mutant analysis, siRNA knockdown","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with catalytic-activity dependency; single lab","pmids":["30683841"],"is_preprint":false},{"year":2021,"finding":"KDM4B physically interacts with c-Myc; the KDM4B-c-Myc complex is co-recruited to c-Myc-binding sequences on promoters of metabolic genes (LDHA, ENO1, PFK) and synergistically promotes transactivation of LDHA in a demethylase-dependent manner.","method":"Co-immunoprecipitation, reporter assay, ChIP, Seahorse metabolic flux analysis, metabolomics","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, and reporter assay with demethylase dependency; single lab","pmids":["34335964"],"is_preprint":false},{"year":2017,"finding":"JMJD2B promotes adipogenesis by removing H3K9me2/3 from the promoters of PPARγ and C/EBPα, activating their expression during 3T3-L1 differentiation.","method":"ChIP, siRNA knockdown, overexpression, adipogenesis assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at PPARγ/C/EBPα promoters with gain/loss-of-function; single lab","pmids":["28060835"],"is_preprint":false},{"year":2018,"finding":"JMJD2B removes H3K9me2/3 from the PPARγ2 promoter to activate its expression and downstream lipogenic target genes, promoting hepatic steatosis. JMJD2B interacts with activated LXRα and is recruited to LXR response elements (LXRE), reducing H3K9me2/3 there to activate LXRα-dependent lipogenesis.","method":"ChIP, co-immunoprecipitation, adenoviral overexpression, siRNA knockdown, reporter assay, in vivo mouse model","journal":"Scientific reports / International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at target promoters, Co-IP with LXRα, in vivo validation; two independent but related studies from same group","pmids":["30214048","33167594"],"is_preprint":false},{"year":2016,"finding":"Neuron-specific deletion of Jmjd2b in mice causes increased total spine number but decreased mature spines in hippocampal CA1, hyperactive behavior, working memory deficits, and spontaneous epileptic-like seizures, establishing KDM4B as a required epigenetic regulator of functional neural circuit development.","method":"Cre-loxP conditional knockout, spine morphology analysis, behavioral testing (open field, maze), EEG","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO with defined morphological and behavioral phenotypes; single lab","pmids":["27023172"],"is_preprint":false},{"year":2020,"finding":"JMJD2B is induced by TGF-β2 and EndMT-promoting/hypoxic conditions in endothelial cells; it mediates site-specific H3K9me3 removal at promoters of mesenchymal genes (CNN1) and TGF-β signaling genes (AKT3, SULF1) to drive endothelial-to-mesenchymal transition. Endothelial-specific deletion of JMJD2B in vivo reduces EndMT after myocardial infarction.","method":"siRNA knockdown, endothelial-specific conditional KO mice, ChIP, endothelial barrier assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo endothelial-specific KO with ChIP and EndMT phenotype; single lab with multiple orthogonal methods","pmids":["32034099"],"is_preprint":false},{"year":2017,"finding":"p-ERK phosphorylates JMJD2B at Thr305, Ser352, Ser566, and Thr1065 under glucose deprivation, stabilizing JMJD2B by protecting it from ubiquitination and proteasomal degradation. The interaction between JMJD2B and p-ERK increases under glucose deprivation.","method":"Co-immunoprecipitation, immunoprecipitation/Western blot for phosphorylation, ubiquitination assay, cell viability assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation site mapping with Co-IP; single lab","pmids":["28945223"],"is_preprint":false},{"year":2020,"finding":"KDM4B interacts with TRAF6 and promotes TRAF6-mediated K63-linked ubiquitination of AKT, leading to AKT activation and upregulation of GLUT1 expression, thereby promoting glucose uptake in colorectal cancer cells.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP, glucose uptake assay","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay demonstrating KDM4B-TRAF6-AKT axis; single lab","pmids":["31931846"],"is_preprint":false},{"year":2012,"finding":"Inducible expression of JMJD2B in mouse ES cells decreased total H3K9me3 by 63%. When these H3K9me3-reduced cells were used as nuclear transfer donors, H3K9me3 was normalized within minutes following fusion with enucleated oocytes, and development into cloned embryos improved by 30%.","method":"Inducible transgenic ES cells, nuclear transfer, immunofluorescence, embryo development assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative H3K9me3 reduction and functional nuclear transfer assay; single lab","pmids":["23263990"],"is_preprint":false},{"year":2014,"finding":"KDM4B interacts with MyoD in C2C12 myoblast cells, is recruited to MyoD and myogenin promoters, and demethylates H3K9me3 there, activating their transcription. Depletion of KDM4B inhibits myogenic differentiation, which is rescued by exogenous MyoD.","method":"Co-immunoprecipitation, ChIP, shRNA knockdown, luciferase reporter, overexpression rescue","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with rescue experiment; single lab","pmids":["25534856"],"is_preprint":false},{"year":2021,"finding":"JMJD2B/KDM4B forms a protein complex with AP-2 family transcription factor TFAP2C and histone demethylase LSD1 in trophoblast stem cells. This complex predominantly occupies active gene promoters. JMJD2B is also associated with loss of H3K36me3 at a subset of embryonic lineage genes marked by H3K9me3 for stable repression.","method":"ChIP-seq, transcriptome analysis, co-immunoprecipitation, siRNA knockdown","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with Co-IP identifying JMJD2B-TFAP2C-LSD1 complex; single lab","pmids":["33441614"],"is_preprint":false},{"year":2023,"finding":"HIF1α transcriptionally activates WTAP, a component of the m6A methyltransferase complex, which in turn increases m6A modification on KDM4B mRNA, stabilizing it. This establishes a HIF1α→WTAP→m6A-KDM4B axis coupling RNA methylation to histone demethylation (H3K9me3) in AML.","method":"ChIP, m6A-seq, mRNA stability assay, siRNA/shRNA knockdown, in vivo xenograft","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A-seq and mRNA stability assay linking WTAP to KDM4B mRNA; single lab with mechanistic pathway","pmids":["37087529"],"is_preprint":false},{"year":2024,"finding":"The deubiquitinase UCHL1 mediates deubiquitination of KDM4B, stabilizing its protein levels. KDM4B binds directly to the VEGFA promoter, removes H3K9me3, and cooperates with HIF2α to activate VEGFA transcription, promoting angiogenesis and bevacizumab resistance in clear cell renal cell carcinoma.","method":"In vivo ubiquitination assay, co-immunoprecipitation, ChIP, luciferase reporter, UCHL1 C90A catalytic mutant","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay with catalytic mutant, ChIP at VEGFA promoter; single lab","pmids":["38743986"],"is_preprint":false},{"year":2019,"finding":"KDM3A and KDM4B co-operate in an auto-regulatory loop in ERα-positive breast cancer; KDM3A primes chromatin for FOXA1 and ER-complex recruitment prior to ER binding. Combined depletion of KDM3A and KDM4B has a greater inhibitory effect on ER activity and cell growth than either alone.","method":"ChIP, siRNA knockdown (individual and combined), global gene expression analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP time-course, combined KD functional assay; single lab","pmids":["31390833"],"is_preprint":false},{"year":2010,"finding":"Full-length JMJD2b-GFP localizes to chromocenters in a manner dependent on SUV39h (its substrate-generating methyltransferase); in SUV39h-deficient cells, chromocenter localization is reduced alongside global H3K9me3 decrease. PHD Zn-finger and Tudor domains of JMJD2b are required for correct chromocenter localization. FRAP reveals ~50% mobile fraction with <1 s recovery; SUV39h deficiency increases the mobile fraction.","method":"GFP fusion live-cell imaging, FRAP, SUV39h knockout cells, truncation/point-mutation analysis","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP with domain-deletion mutants in isogenic genetic backgrounds; single lab","pmids":["21073875"],"is_preprint":false},{"year":2017,"finding":"KDM4B is recruited to the ICAM1 and VCAM1 promoters upon TNF-α stimulation, removes H3K9me2, and is required for TNF-α-induced upregulation of these vascular adhesion molecules and subsequent leukocyte adhesion/transmigration in brain microvascular endothelial cells.","method":"ChIP, siRNA knockdown, KDM4 inhibitor (ML324), leukocyte adhesion/transmigration assay, in vivo neutrophil adhesion","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at ICAM1/VCAM1 with siRNA and pharmacological inhibition; single lab","pmids":["28327608"],"is_preprint":false},{"year":2019,"finding":"JMJD2B depletion causes spontaneous DNA double-strand breaks and radiosensitizes colorectal cancer cells through suppression of STAT3 signaling; STAT3 overexpression in KDM4B-knockdown cells attenuates DNA damage and restores cell survival. CREB transcription factor directly binds the KDM4B promoter to drive its expression.","method":"ChIP, siRNA knockdown/overexpression, γH2AX foci, STAT3 pathway western blot, clonogenic assay","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP for CREB at KDM4B promoter and epistasis via STAT3 OE; single lab, limited mechanistic depth","pmids":["29633065"],"is_preprint":false}],"current_model":"KDM4B (JMJD2B) is a Jumonji-C domain histone lysine demethylase that primarily removes H3K9me3/me2 (and to a lesser extent H3K36me3) to activate gene transcription; it is induced by HIF-1α under hypoxia and by steroid hormones (estrogen, androgen), forms functional complexes with ERα/MLL2, AR, C/EBPβ, c-Jun, c-Myc, N-Myc, NF-κB p65, GATA-3, and MyoD at target gene promoters, and is regulated post-translationally by Hsp90-dependent stabilization, SCF^Fbxo22-mediated ubiquitination/degradation, ERK-mediated phosphorylation, and UCHL1-mediated deubiquitination; it additionally functions as a DNA damage response protein recruited to double-strand breaks in a PARP1-dependent manner, and acts non-canonically as a PKA-phosphorylated splicing scaffold that promotes AR-V7 generation and as a cytoplasmic regulator of eIF2α phosphorylation to control the unfolded protein response."},"narrative":{"mechanistic_narrative":"KDM4B (JMJD2B) is a Jumonji-C domain histone lysine demethylase that actively removes repressive H3K9me3/me2 (and H3K36 methylation) at pericentric heterochromatin and gene-regulatory regions to control chromatin state and transcription [PMID:16738407, PMID:21073875]. Its catalytic architecture and K9/K36 selectivity were defined by a ternary crystal structure with H3K9me3 peptide and a 2,4-PDCA inhibitor [PMID:24971742]. Chromocenter targeting depends on its PHD and Tudor domains and on the substrate-generating methyltransferase SUV39h, coupling its localization to the H3K9me3 mark it erases [PMID:21073875]. Functionally, KDM4B acts as a transcriptional coactivator that demethylates H3K9me3 at promoters and enhancers bound by lineage and signal-responsive transcription factors, and at ERα target genes its H3K9 demethylation is a prerequisite for MLL2-mediated H3K4 methylation, enforcing mutual exclusivity of the two marks [PMID:21502505, PMID:21445275]. Across cell types it partners with sequence-specific factors—ERα, AR, GATA-3, C/EBPβ, MyoD, c-Jun, c-Myc/N-Myc, NF-κB p65, β-catenin/TCF4, and TFAP2C/LSD1—to derepress target loci, driving programs from steroid-responsive growth to mesenchymal/skeletal differentiation [PMID:23723241, PMID:22722334, PMID:24481461, PMID:34031372, PMID:25925418, PMID:25534856, PMID:33441614]. KDM4B is itself an induced effector node: HIF-1α, p53, and steroid receptors transcriptionally activate it [PMID:18984585, PMID:28073943, PMID:23435229], while its protein stability is set by Hsp90 binding, SCF^Fbxo22 ubiquitination, ERK phosphorylation, and UCHL1 deubiquitination [PMID:23589305, PMID:30418174, PMID:28945223, PMID:38743986]. In stem and progenitor cells it sustains ESC self-renewal within the Nanog regulatory module and directs mesenchymal stem cell fate toward osteo/chondrogenesis via H3K9me3 removal at DLX and SOX9 loci [PMID:24361252, PMID:22770241, PMID:26485430, PMID:33571444]. KDM4B also has non-canonical activities: PARP1-dependent recruitment to double-strand breaks promoting heterochromatin repair [PMID:23744078], a PKA-phosphorylated splicing-scaffold role coupling the spliceosome to chromatin to generate AR-V7 [PMID:31647098], and a cytoplasmic interaction with eIF2α that restrains the unfolded protein response [PMID:30266800].","teleology":[{"year":2006,"claim":"Established that KDM4B is a bona fide enzyme that actively removes H3K9me3 in living cells, defining its core catalytic function before downstream biology could be assigned.","evidence":"Inducible Jmjd2b-GFP lines with SILAC heavy-methyl metabolic labeling and immunofluorescence at pericentric heterochromatin","pmids":["16738407"],"confidence":"High","gaps":["Poor in vitro activity left the physiological substrate kinetics unresolved","Did not address gene-specific transcriptional consequences"]},{"year":2008,"claim":"Identified KDM4B as a direct HIF-1α transcriptional target, placing the demethylase downstream of hypoxic signaling.","evidence":"ChIP of HIF-1α at the JMJD2B promoter, reporter assays, and demethylase activity confirmation under hypoxia","pmids":["18984585"],"confidence":"High","gaps":["Downstream genes regulated by hypoxia-induced KDM4B not mapped here"]},{"year":2010,"claim":"Defined how KDM4B finds its substrate, showing localization depends on its reader domains and on SUV39h-generated H3K9me3.","evidence":"GFP-fusion live-cell imaging, FRAP, and truncation/point mutants in SUV39h-deficient cells","pmids":["21073875"],"confidence":"Medium","gaps":["Did not establish whether reader-domain mutants disrupt catalytic turnover","Mobility measured only at chromocenters"]},{"year":2012,"claim":"Connected H3K9me3 removal to specific differentiation programs, showing KDM4B activates DLX (osteogenesis), adipogenic, and cell-cycle gene loci as a transcription-factor cofactor.","evidence":"ChIP, Co-IP, EMSA, reporter assays and in vivo ovariectomized/aging mouse models in MSCs and 3T3-L1 cells","pmids":["22770241","22722334"],"confidence":"High","gaps":["Mechanism of recruitment to individual TF complexes not fully separated from genome-wide effects"]},{"year":2013,"claim":"Revealed KDM4B as a multi-functional transcriptional coactivator across nuclear-receptor and lineage pathways and a DNA-damage-response factor, including a catalysis-independent role in stabilizing AR protein.","evidence":"Co-IP, ChIP, ubiquitination assays, demethylase-dead mutants, laser micro-irradiation with PARP inhibition (ERα/MLL2, AR, GATA-3, β-catenin, DSB systems)","pmids":["21502505","21445275","23435229","23723241","23744078","24077348"],"confidence":"High","gaps":["Whether the H3K4/H3K9 mark coordination is direct or sequential at single loci not resolved","Catalysis-independent AR stabilization mechanism (E3 ligase blocked) not identified"]},{"year":2013,"claim":"Placed KDM4B in a p53 feedback circuit, linking the demethylase both to attenuation of p53 transcriptional output and to heterochromatin repair after DNA damage.","evidence":"ChIP of p53 at the JMJD2B promoter, siRNA, reporters, IR survival assays","pmids":["28073943","23376847"],"confidence":"Medium","gaps":["Single-lab studies; physiological context of the p53–KDM4B loop in normal tissue unclear"]},{"year":2013,"claim":"Showed KDM4B is required for pluripotency and reprogramming, integrating it into the core Nanog regulatory network.","evidence":"RNAi screen, genome-wide ChIP-seq occupancy, and iPS reprogramming assays in mouse ESCs","pmids":["24361252"],"confidence":"High","gaps":["Degree of functional redundancy with KDM4C not fully partitioned"]},{"year":2014,"claim":"Solved the catalytic architecture, providing a structural basis for K9/K36 selectivity and a template for inhibitor design.","evidence":"X-ray crystallography of the KDM4B/2,4-PDCA/H3K9me3 ternary complex with inhibition and ChIP validation","pmids":["24971742"],"confidence":"High","gaps":["Structure of full-length enzyme with reader domains not determined"]},{"year":2014,"claim":"Mapped the Hsp90 chaperone and β-catenin/MyoD interactions, defining post-translational stabilization and additional lineage-specific coactivator roles.","evidence":"Co-IP, ubiquitination-site mutagenesis (K337/K562), geldanamycin treatment, domain mapping, ChIP and rescue in myoblasts","pmids":["23589305","24481461","25534856"],"confidence":"Medium","gaps":["The cognate E3 ligase for basal/geldanamycin-induced ubiquitination not identified here"]},{"year":2018,"claim":"Uncovered non-canonical cytoplasmic and degradation-control functions: restraint of eIF2α phosphorylation/UPR and SCF^Fbxo22-dependent degradation that underlies tamoxifen antagonism.","evidence":"Cytoplasmic Co-IP with eIF2α, UPR/apoptosis assays, ubiquitination assays, live-cell FRET/BiFC and ChIP in ERα systems","pmids":["30266800","30418174"],"confidence":"High","gaps":["How demethylase activity is required for a cytoplasmic eIF2α function is mechanistically unexplained","Substrate(s) bridging KDM4B to Fbxo22 recognition not fully defined"]},{"year":2019,"claim":"Defined a chromatin-coupled splicing scaffold activity, showing PKA-phosphorylated KDM4B binds SF3B3 and AR pre-mRNA to generate the AR-V7 variant driving castration resistance.","evidence":"IP, RIP, ATAC-seq, genome-wide splicing profiling and phosphorylation mapping","pmids":["31647098"],"confidence":"High","gaps":["Generality of the splicing-scaffold role beyond AR not tested","Relationship between this activity and demethylase catalysis unresolved"]},{"year":2021,"claim":"Extended KDM4B into telomere maintenance and bone remodeling, showing its inactivation drives ALT and its complex with CCAR1/MED1 recruits NF-κB p65 for osteoclastogenesis.","evidence":"Genetic KO/overexpression in ESC and ALT models; ChIP-seq, Co-IP, myeloid conditional KO and inhibitor treatment","pmids":["33972520","34031372","33571444"],"confidence":"High","gaps":["Direct molecular link between KDM4B loss and the ALT recombination machinery not delineated"]},{"year":2024,"claim":"Completed the regulatory loop around KDM4B stability and angiogenic output, adding UCHL1 deubiquitination and an m6A/WTAP mRNA-stabilization axis upstream, with VEGFA/HIF2α downstream.","evidence":"Ubiquitination assays with UCHL1 catalytic mutant, m6A-seq, mRNA stability assays, ChIP at VEGFA promoter, xenografts","pmids":["38743986","37087529"],"confidence":"Medium","gaps":["Single-lab studies; interplay of competing stabilizing/destabilizing inputs not integrated quantitatively"]},{"year":null,"claim":"How KDM4B's distinct activities—nuclear demethylase, DSB-repair factor, cytoplasmic eIF2α regulator, and splicing scaffold—are selected in a given cell state, and which inputs dominate its competing stabilization/degradation pathways, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model integrating catalytic and non-catalytic functions","Determinants of nuclear vs cytoplasmic partitioning unknown","Quantitative hierarchy among Hsp90/Fbxo22/ERK/UCHL1/m6A regulation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,7]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,11,36]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[41]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,41]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,2,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,41]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,14,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,9,19,36]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7,13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[23]}],"complexes":["MLL2 H3K4 methyltransferase complex","KDM4B-CCAR1-MED1 complex","JMJD2B-TFAP2C-LSD1 complex"],"partners":["ESR1","AR","GATA3","CEBPB","CTNNB1","MYOD1","HSP90","EIF2AK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O94953","full_name":"Lysine-specific demethylase 4B","aliases":["JmjC domain-containing histone demethylation protein 3B","Jumonji domain-containing protein 2B","[histone H3]-trimethyl-L-lysine(9) demethylase 4B"],"length_aa":1096,"mass_kda":121.9,"function":"Histone demethylase that specifically demethylates 'Lys-9' of histone H3, thereby playing a role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27', H3 'Lys-36' nor H4 'Lys-20'. Only able to demethylate trimethylated H3 'Lys-9', with a weaker activity than KDM4A, KDM4C and KDM4D. Demethylation of Lys residue generates formaldehyde and succinate (PubMed:16603238, PubMed:28262558). Plays a critical role in the development of the central nervous system (CNS)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/O94953/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM4B","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KDM4B","total_profiled":1310},"omim":[{"mim_id":"621184","title":"TAYOUN-MAAWALI SYNDROME; TYMAS","url":"https://www.omim.org/entry/621184"},{"mim_id":"619320","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 65; MRD65","url":"https://www.omim.org/entry/619320"},{"mim_id":"609765","title":"LYSINE DEMETHYLASE 4B; KDM4B","url":"https://www.omim.org/entry/609765"},{"mim_id":"609096","title":"F-BOX ONLY PROTEIN 22; FBXO22","url":"https://www.omim.org/entry/609096"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM4B"},"hgnc":{"alias_symbol":["KIAA0876","TDRD14B"],"prev_symbol":["JMJD2B"]},"alphafold":{"accession":"O94953","domains":[{"cath_id":"2.60.120.650","chopping":"17-58_69-351","consensus_level":"high","plddt":92.8518,"start":17,"end":351},{"cath_id":"3.30.40.10","chopping":"652-698_720-741_748-907","consensus_level":"high","plddt":84.9684,"start":652,"end":907},{"cath_id":"2.30.30.140","chopping":"924-1037","consensus_level":"high","plddt":84.3451,"start":924,"end":1037}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O94953","model_url":"https://alphafold.ebi.ac.uk/files/AF-O94953-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O94953-F1-predicted_aligned_error_v6.png","plddt_mean":69.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM4B","jax_strain_url":"https://www.jax.org/strain/search?query=KDM4B"},"sequence":{"accession":"O94953","fasta_url":"https://rest.uniprot.org/uniprotkb/O94953.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O94953/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O94953"}},"corpus_meta":[{"pmid":"16738407","id":"PMC_16738407","title":"Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells.","date":"2006","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/16738407","citation_count":303,"is_preprint":false},{"pmid":"22770241","id":"PMC_22770241","title":"Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs.","date":"2012","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/22770241","citation_count":286,"is_preprint":false},{"pmid":"18984585","id":"PMC_18984585","title":"The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18984585","citation_count":284,"is_preprint":false},{"pmid":"21502505","id":"PMC_21502505","title":"Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21502505","citation_count":216,"is_preprint":false},{"pmid":"21445275","id":"PMC_21445275","title":"Histone demethylase JMJD2B functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21445275","citation_count":157,"is_preprint":false},{"pmid":"20682797","id":"PMC_20682797","title":"The histone demethylase JMJD2B is regulated by estrogen receptor alpha and hypoxia, and is a key mediator of estrogen induced growth.","date":"2010","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/20682797","citation_count":153,"is_preprint":false},{"pmid":"33571444","id":"PMC_33571444","title":"Loss of KDM4B exacerbates bone-fat imbalance and mesenchymal stromal cell exhaustion in skeletal aging.","date":"2021","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/33571444","citation_count":142,"is_preprint":false},{"pmid":"23744078","id":"PMC_23744078","title":"Kdm4b histone demethylase is a DNA damage response protein and confers a survival advantage following γ-irradiation.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23744078","citation_count":126,"is_preprint":false},{"pmid":"23435229","id":"PMC_23435229","title":"The lysine demethylase, KDM4B, is a key molecule in androgen receptor signalling and turnover.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23435229","citation_count":106,"is_preprint":false},{"pmid":"24361252","id":"PMC_24361252","title":"Distinct and combinatorial functions of Jmjd2b/Kdm4b and Jmjd2c/Kdm4c in mouse embryonic stem cell identity.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24361252","citation_count":105,"is_preprint":false},{"pmid":"32684087","id":"PMC_32684087","title":"Enterotoxigenic Bacteroides fragilis induces the stemness in colorectal cancer via upregulating histone demethylase JMJD2B.","date":"2020","source":"Gut microbes","url":"https://pubmed.ncbi.nlm.nih.gov/32684087","citation_count":99,"is_preprint":false},{"pmid":"24077348","id":"PMC_24077348","title":"JMJD2B promotes epithelial-mesenchymal transition by cooperating with β-catenin and enhances gastric cancer metastasis.","date":"2013","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/24077348","citation_count":95,"is_preprint":false},{"pmid":"30981888","id":"PMC_30981888","title":"IL-6 and sIL-6R induces STAT3-dependent differentiation of human VSMCs into osteoblast-like cells through JMJD2B-mediated histone demethylation of RUNX2.","date":"2019","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/30981888","citation_count":91,"is_preprint":false},{"pmid":"24971742","id":"PMC_24971742","title":"KDM4B as a target for prostate cancer: structural analysis and selective inhibition by a novel inhibitor.","date":"2014","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24971742","citation_count":84,"is_preprint":false},{"pmid":"22745382","id":"PMC_22745382","title":"HIF-1α-induced histone demethylase JMJD2B contributes to the malignant phenotype of colorectal cancer cells via an epigenetic mechanism.","date":"2012","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/22745382","citation_count":76,"is_preprint":false},{"pmid":"23723241","id":"PMC_23723241","title":"KDM4B is a master regulator of the estrogen receptor signalling cascade.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23723241","citation_count":71,"is_preprint":false},{"pmid":"22133676","id":"PMC_22133676","title":"Histone demethylase JMJD2B is required for tumor cell proliferation and survival and is overexpressed in gastric cancer.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22133676","citation_count":65,"is_preprint":false},{"pmid":"21930796","id":"PMC_21930796","title":"The histone demethylase JMJD2B plays an essential role in human carcinogenesis through positive regulation of cyclin-dependent kinase 6.","date":"2011","source":"Cancer prevention research (Philadelphia, Pa.)","url":"https://pubmed.ncbi.nlm.nih.gov/21930796","citation_count":60,"is_preprint":false},{"pmid":"25925418","id":"PMC_25925418","title":"The role of histone demethylase KDM4B in Myc signaling in neuroblastoma.","date":"2015","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/25925418","citation_count":59,"is_preprint":false},{"pmid":"23376847","id":"PMC_23376847","title":"p53 promotes repair of heterochromatin DNA by regulating JMJD2b and SUV39H1 expression.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23376847","citation_count":57,"is_preprint":false},{"pmid":"22722334","id":"PMC_22722334","title":"Histone demethylase Kdm4b functions as a co-factor of C/EBPβ to promote mitotic clonal expansion during differentiation of 3T3-L1 preadipocytes.","date":"2012","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/22722334","citation_count":57,"is_preprint":false},{"pmid":"26485430","id":"PMC_26485430","title":"Transforming Growth Factor-β-Induced KDM4B Promotes Chondrogenic Differentiation of Human Mesenchymal Stem Cells.","date":"2015","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/26485430","citation_count":56,"is_preprint":false},{"pmid":"31647098","id":"PMC_31647098","title":"Histone lysine demethylase KDM4B regulates the alternative splicing of the androgen receptor in response to androgen deprivation.","date":"2019","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31647098","citation_count":56,"is_preprint":false},{"pmid":"23263990","id":"PMC_23263990","title":"Transient JMJD2B-mediated reduction of H3K9me3 levels improves reprogramming of embryonic stem cells into cloned embryos.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23263990","citation_count":55,"is_preprint":false},{"pmid":"29844188","id":"PMC_29844188","title":"KDM4B protects against obesity and metabolic dysfunction.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29844188","citation_count":52,"is_preprint":false},{"pmid":"27869162","id":"PMC_27869162","title":"The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27869162","citation_count":52,"is_preprint":false},{"pmid":"32034099","id":"PMC_32034099","title":"The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32034099","citation_count":49,"is_preprint":false},{"pmid":"31931846","id":"PMC_31931846","title":"KDM4B facilitates colorectal cancer growth and glucose metabolism by stimulating TRAF6-mediated AKT activation.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31931846","citation_count":47,"is_preprint":false},{"pmid":"30418174","id":"PMC_30418174","title":"Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer.","date":"2018","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30418174","citation_count":47,"is_preprint":false},{"pmid":"30759871","id":"PMC_30759871","title":"KDM4B: A Nail for Every Hammer?","date":"2019","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/30759871","citation_count":46,"is_preprint":false},{"pmid":"24481461","id":"PMC_24481461","title":"Stimulation of β-catenin and colon cancer cell growth by the KDM4B histone demethylase.","date":"2014","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24481461","citation_count":46,"is_preprint":false},{"pmid":"33972520","id":"PMC_33972520","title":"Mutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33972520","citation_count":44,"is_preprint":false},{"pmid":"25725194","id":"PMC_25725194","title":"miR-491-5p functions as a tumor suppressor by targeting JMJD2B in ERα-positive breast cancer.","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/25725194","citation_count":44,"is_preprint":false},{"pmid":"34335964","id":"PMC_34335964","title":"Targeting KDM4B that coactivates c-Myc-regulated metabolism to suppress tumor growth in castration-resistant prostate cancer.","date":"2021","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/34335964","citation_count":41,"is_preprint":false},{"pmid":"30266800","id":"PMC_30266800","title":"KDM4B-regulated unfolded protein response as a therapeutic vulnerability in PTEN-deficient breast cancer.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30266800","citation_count":38,"is_preprint":false},{"pmid":"23046878","id":"PMC_23046878","title":"Histone demethylase JMJD2B-mediated cell proliferation regulated by hypoxia and radiation in gastric cancer cell.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23046878","citation_count":37,"is_preprint":false},{"pmid":"22120968","id":"PMC_22120968","title":"Triptolide induces cell-cycle arrest and apoptosis of human multiple myeloma cells in vitro via altering expression of histone demethylase LSD1 and JMJD2B.","date":"2011","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/22120968","citation_count":37,"is_preprint":false},{"pmid":"30459150","id":"PMC_30459150","title":"Histone Demethylase KDM4B Promotes DNA Damage by Activating Long Interspersed Nuclear Element-1.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30459150","citation_count":36,"is_preprint":false},{"pmid":"27487123","id":"PMC_27487123","title":"KDM4B-mediated epigenetic silencing of miRNA-615-5p augments RAB24 to facilitate malignancy of hepatoma cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27487123","citation_count":36,"is_preprint":false},{"pmid":"28945223","id":"PMC_28945223","title":"Role of JMJD2B in colon cancer cell survival under glucose-deprived conditions and the underlying mechanisms.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28945223","citation_count":35,"is_preprint":false},{"pmid":"31468537","id":"PMC_31468537","title":"Upregulated KDM4B promotes prostate cancer cell proliferation by activating autophagy.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31468537","citation_count":34,"is_preprint":false},{"pmid":"30683841","id":"PMC_30683841","title":"KDM4B is a coactivator of c-Jun and involved in gastric carcinogenesis.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30683841","citation_count":34,"is_preprint":false},{"pmid":"30214048","id":"PMC_30214048","title":"Histone H3K9 demethylase JMJD2B induces hepatic steatosis through upregulation of PPARγ2.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30214048","citation_count":34,"is_preprint":false},{"pmid":"17611647","id":"PMC_17611647","title":"Comparative integromics on JMJD2A, JMJD2B and JMJD2C: preferential expression of JMJD2C in undifferentiated ES cells.","date":"2007","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17611647","citation_count":34,"is_preprint":false},{"pmid":"28073943","id":"PMC_28073943","title":"KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage.","date":"2017","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/28073943","citation_count":33,"is_preprint":false},{"pmid":"28060835","id":"PMC_28060835","title":"Histone H3K9 Demethylase JMJD2B Activates Adipogenesis by Regulating H3K9 Methylation on PPARγ and C/EBPα during Adipogenesis.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28060835","citation_count":33,"is_preprint":false},{"pmid":"33732698","id":"PMC_33732698","title":"MicroRNA-15a Carried by Mesenchymal Stem Cell-Derived Extracellular Vesicles Inhibits the Immune Evasion of Colorectal Cancer Cells by Regulating the KDM4B/HOXC4/PD-L1 Axis.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33732698","citation_count":33,"is_preprint":false},{"pmid":"28790329","id":"PMC_28790329","title":"KDM4B-mediated reduction of H3K9me3 and H3K36me3 levels improves somatic cell reprogramming into pluripotency.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28790329","citation_count":32,"is_preprint":false},{"pmid":"33167594","id":"PMC_33167594","title":"Histone H3K9 Demethylase JMJD2B Plays a Role in LXRα-Dependent Lipogenesis.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33167594","citation_count":32,"is_preprint":false},{"pmid":"27023172","id":"PMC_27023172","title":"Deletion of JMJD2B in neurons leads to defective spine maturation, hyperactive behavior and memory deficits in mouse.","date":"2016","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/27023172","citation_count":32,"is_preprint":false},{"pmid":"23589305","id":"PMC_23589305","title":"Heat shock protein 90 (Hsp90) selectively regulates the stability of KDM4B/JMJD2B histone demethylase.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23589305","citation_count":31,"is_preprint":false},{"pmid":"27232941","id":"PMC_27232941","title":"JMJD2B is required for Helicobacter pylori-induced gastric carcinogenesis via regulating COX-2 expression.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27232941","citation_count":30,"is_preprint":false},{"pmid":"32617978","id":"PMC_32617978","title":"Targeting the KDM4B-AR-c-Myc axis promotes sensitivity to androgen receptor-targeted therapy in advanced prostate cancer.","date":"2020","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32617978","citation_count":30,"is_preprint":false},{"pmid":"35186950","id":"PMC_35186950","title":"The Diverse Roles of Histone Demethylase KDM4B in Normal and Cancer Development and Progression.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35186950","citation_count":29,"is_preprint":false},{"pmid":"25607726","id":"PMC_25607726","title":"Emodin attenuates radioresistance induced by hypoxia in HepG2 cells via the enhancement of PARP1 cleavage and inhibition of JMJD2B.","date":"2015","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25607726","citation_count":29,"is_preprint":false},{"pmid":"34031372","id":"PMC_34031372","title":"The KDM4B-CCAR1-MED1 axis is a critical regulator of osteoclast differentiation and bone homeostasis.","date":"2021","source":"Bone research","url":"https://pubmed.ncbi.nlm.nih.gov/34031372","citation_count":28,"is_preprint":false},{"pmid":"32483417","id":"PMC_32483417","title":"JMJD2B-induced amino acid alterations enhance the survival of colorectal cancer cells under glucose-deprivation via autophagy.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32483417","citation_count":27,"is_preprint":false},{"pmid":"29511447","id":"PMC_29511447","title":"MiRNA-491-5p inhibits cell proliferation, invasion and migration via targeting JMJD2B and serves as a potential biomarker in gastric cancer.","date":"2018","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/29511447","citation_count":27,"is_preprint":false},{"pmid":"26511091","id":"PMC_26511091","title":"KDM4B promotes epithelial-mesenchymal transition through up-regulation of ZEB1 in pancreatic cancer.","date":"2015","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/26511091","citation_count":27,"is_preprint":false},{"pmid":"24957706","id":"PMC_24957706","title":"Silencing of JMJD2B induces cell apoptosis via mitochondria-mediated and death receptor-mediated pathway activation in colorectal cancer.","date":"2014","source":"Journal of digestive diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24957706","citation_count":26,"is_preprint":false},{"pmid":"26722485","id":"PMC_26722485","title":"KDM4A, KDM4B and KDM4C in non-small cell lung cancer.","date":"2015","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26722485","citation_count":26,"is_preprint":false},{"pmid":"28327608","id":"PMC_28327608","title":"KDM4B histone demethylase and G9a regulate expression of vascular adhesion proteins in cerebral microvessels.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28327608","citation_count":26,"is_preprint":false},{"pmid":"30503866","id":"PMC_30503866","title":"Distal-less homeobox 5 promotes the osteo-/dentinogenic differentiation potential of stem cells from apical papilla by activating histone demethylase KDM4B through a positive feedback mechanism.","date":"2018","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30503866","citation_count":26,"is_preprint":false},{"pmid":"33232677","id":"PMC_33232677","title":"Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects.","date":"2020","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33232677","citation_count":25,"is_preprint":false},{"pmid":"26397136","id":"PMC_26397136","title":"KDM4B and KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, and p27kip1.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26397136","citation_count":25,"is_preprint":false},{"pmid":"27506941","id":"PMC_27506941","title":"KDM4B plays an important role in mitochondrial apoptosis by upregulating HAX1 expression in colorectal cancer.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27506941","citation_count":25,"is_preprint":false},{"pmid":"29633065","id":"PMC_29633065","title":"KDM4B promotes DNA damage response via STAT3 signaling and is a target of CREB in colorectal cancer cells.","date":"2018","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29633065","citation_count":24,"is_preprint":false},{"pmid":"29342868","id":"PMC_29342868","title":"Hypoxia and Hormone-Mediated Pathways Converge at the Histone Demethylase KDM4B in Cancer.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29342868","citation_count":23,"is_preprint":false},{"pmid":"29927684","id":"PMC_29927684","title":"Inhibition of the histone demethylase KDM4B leads to activation of KDM1A, attenuates bacterial-induced pro-inflammatory cytokine release, and reduces osteoclastogenesis.","date":"2018","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29927684","citation_count":23,"is_preprint":false},{"pmid":"37087529","id":"PMC_37087529","title":"HIF1α-mediated transactivation of WTAP promotes AML cell proliferation via m6A-dependent stabilization of KDM4B mRNA.","date":"2023","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/37087529","citation_count":22,"is_preprint":false},{"pmid":"28928876","id":"PMC_28928876","title":"Heterochromatin Reduction Correlates with the Increase of the KDM4B and KDM6A Demethylases and the Expression of Pericentromeric DNA during the Acquisition of a Transformed Phenotype.","date":"2017","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/28928876","citation_count":22,"is_preprint":false},{"pmid":"30073721","id":"PMC_30073721","title":"JMJD2B/KDM4B inactivation in adipose tissues accelerates obesity and systemic metabolic abnormalities.","date":"2018","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/30073721","citation_count":21,"is_preprint":false},{"pmid":"30485532","id":"PMC_30485532","title":"KDM4B promotes gastric cancer metastasis by regulating miR-125b-mediated activation of Wnt signaling.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30485532","citation_count":21,"is_preprint":false},{"pmid":"31390833","id":"PMC_31390833","title":"The Histone Demethylase Enzymes KDM3A and KDM4B Co-Operatively Regulate Chromatin Transactions of the Estrogen Receptor in Breast Cancer.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31390833","citation_count":20,"is_preprint":false},{"pmid":"26598618","id":"PMC_26598618","title":"Histone demethylase KDM4B regulates otic vesicle invagination via epigenetic control of Dlx3 expression.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26598618","citation_count":19,"is_preprint":false},{"pmid":"22388778","id":"PMC_22388778","title":"TSA-induced JMJD2B downregulation is associated with cyclin B1-dependent survivin degradation and apoptosis in LNCap cells.","date":"2012","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22388778","citation_count":19,"is_preprint":false},{"pmid":"25533242","id":"PMC_25533242","title":"JMJD2B as a potential diagnostic immunohistochemical marker for hepatocellular carcinoma: a tissue microarray-based study.","date":"2014","source":"Acta histochemica","url":"https://pubmed.ncbi.nlm.nih.gov/25533242","citation_count":18,"is_preprint":false},{"pmid":"34249900","id":"PMC_34249900","title":"Activation of TC10-Like Transcription by Lysine Demethylase KDM4B in Colorectal Cancer Cells.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34249900","citation_count":18,"is_preprint":false},{"pmid":"25636512","id":"PMC_25636512","title":"Histone demethylase JMJD2B and JMJD2C induce fibroblast growth factor 2: mediated tumorigenesis of osteosarcoma.","date":"2015","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25636512","citation_count":17,"is_preprint":false},{"pmid":"27630312","id":"PMC_27630312","title":"Strong KDM4B and KDM4D Expression Associates with Radioresistance and Aggressive Phenotype in Classical Hodgkin Lymphoma.","date":"2016","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27630312","citation_count":17,"is_preprint":false},{"pmid":"25534856","id":"PMC_25534856","title":"The histone demethylase KDM4B interacts with MyoD to regulate myogenic differentiation in C2C12 myoblast cells.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25534856","citation_count":16,"is_preprint":false},{"pmid":"32594337","id":"PMC_32594337","title":"Osmolarity controls the differentiation of adipose-derived stem cells into nucleus pulposus cells via histone demethylase KDM4B.","date":"2020","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32594337","citation_count":16,"is_preprint":false},{"pmid":"22890720","id":"PMC_22890720","title":"Functional analysis of histone demethylase Jmjd2b on lipopolysaccharide-treated murine neural stem cells (NSCs).","date":"2012","source":"Neurotoxicity research","url":"https://pubmed.ncbi.nlm.nih.gov/22890720","citation_count":15,"is_preprint":false},{"pmid":"32856377","id":"PMC_32856377","title":"Inhibition of microRNA-27b-3p relieves osteoarthritis pain via regulation of KDM4B-dependent DLX5.","date":"2020","source":"BioFactors (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32856377","citation_count":15,"is_preprint":false},{"pmid":"36217382","id":"PMC_36217382","title":"Histone H3K9 demethylase JMJD2B/KDM4B promotes osteogenic differentiation of bone marrow-derived mesenchymal stem cells by regulating H3K9me2 on RUNX2.","date":"2022","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/36217382","citation_count":14,"is_preprint":false},{"pmid":"33441614","id":"PMC_33441614","title":"Histone demethylase JMJD2B/KDM4B regulates transcriptional program via distinctive epigenetic targets and protein interactors for the maintenance of trophoblast stem cells.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33441614","citation_count":14,"is_preprint":false},{"pmid":"31036564","id":"PMC_31036564","title":"The histone demethylase JMJD2B is critical for p53-mediated autophagy and survival in Nutlin-treated cancer cells.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31036564","citation_count":12,"is_preprint":false},{"pmid":"38859856","id":"PMC_38859856","title":"circBRAF promotes the progression of triple-negative breast cancer through modulating methylation by recruiting KDM4B to histone H3K9me3 and IGF2BP3 to mRNA.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38859856","citation_count":12,"is_preprint":false},{"pmid":"37923555","id":"PMC_37923555","title":"KDM4B: A promising oncology therapeutic target.","date":"2023","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/37923555","citation_count":11,"is_preprint":false},{"pmid":"38093312","id":"PMC_38093312","title":"Histone demethylase KDM4B accelerates the progression of glioblastoma via the epigenetic regulation of MYC stability.","date":"2023","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/38093312","citation_count":10,"is_preprint":false},{"pmid":"34425304","id":"PMC_34425304","title":"Effects of demethylase KDM4B on the biological characteristics and function of yak cumulus cells in vitro.","date":"2021","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/34425304","citation_count":10,"is_preprint":false},{"pmid":"38950776","id":"PMC_38950776","title":"Super-enhancer-driven LncRNA PPARα-seRNA exacerbates glucolipid metabolism and diabetic cardiomyopathy via recruiting KDM4B.","date":"2024","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38950776","citation_count":9,"is_preprint":false},{"pmid":"37249813","id":"PMC_37249813","title":"KDM4B down-regulation facilitated breast cancer cell stemness via PHGDH upregulation in H3K36me3-dependent manner.","date":"2023","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37249813","citation_count":9,"is_preprint":false},{"pmid":"36495660","id":"PMC_36495660","title":"Therapeutic targeting of histone lysine demethylase KDM4B blocks the growth of castration-resistant prostate cancer.","date":"2022","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/36495660","citation_count":9,"is_preprint":false},{"pmid":"21073875","id":"PMC_21073875","title":"Mutant genetic background affects the functional rearrangement and kinetic properties of JMJD2b histone demethylase.","date":"2010","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21073875","citation_count":9,"is_preprint":false},{"pmid":"39433954","id":"PMC_39433954","title":"H3K9me3 demethylation by JMJD2B is regulated by pirfenidone resulting in improved NASH.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39433954","citation_count":8,"is_preprint":false},{"pmid":"34938963","id":"PMC_34938963","title":"KDM4B promotes acute myeloid leukemia associated with AML1-ETO by regulating chromatin accessibility.","date":"2021","source":"FASEB bioAdvances","url":"https://pubmed.ncbi.nlm.nih.gov/34938963","citation_count":8,"is_preprint":false},{"pmid":"33909202","id":"PMC_33909202","title":"KDM4B Overexpression Promotes the Growth, Migration, and Invasion of Rheumatoid Arthritis Fibroblast-Like Synoviocytes by Activating STAT3 Pathway.","date":"2021","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33909202","citation_count":8,"is_preprint":false},{"pmid":"29536385","id":"PMC_29536385","title":"Histone demethylase KDM4A and KDM4B expression in granulosa cells from women undergoing in vitro fertilization.","date":"2018","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29536385","citation_count":7,"is_preprint":false},{"pmid":"38743986","id":"PMC_38743986","title":"Deubiquitinase UCHL1 stabilizes KDM4B to augment VEGF signaling and confer bevacizumab resistance in clear cell renal cell carcinoma.","date":"2024","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38743986","citation_count":7,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52006,"output_tokens":10524,"usd":0.156939,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20960,"output_tokens":4911,"usd":0.113787,"stage2_stop_reason":"end_turn"},"total_usd":0.270726,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Jmjd2b (KDM4B) actively removes H3K9me3 at pericentric heterochromatin in mammalian cells; metabolic labeling with heavy methyl groups demonstrated this is an active demethylation process occurring before DNA replication. Recombinant Jmjd2b appeared as a poor enzyme in vitro, yet also reduced H3K36 methylation.\",\n      \"method\": \"Inducible Jmjd2b-GFP cell lines, metabolic labeling with heavy methyl groups (SILAC-based), immunofluorescence\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct metabolic labeling demonstrated active H3K9me3 removal in vivo; replicated by multiple labs subsequently\",\n      \"pmids\": [\"16738407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JMJD2B (KDM4B) is an integral component of the MLL2 H3K4 methyltransferase complex and co-purifies with estrogen receptor α (ERα). H3K9 demethylation by JMJD2B is a prerequisite for H3K4 methylation at ERα target gene promoters, coordinating the mutual exclusivity of H3K9 and H3K4 methylation during ERα-activated transcription.\",\n      \"method\": \"Affinity purification/co-purification, ChIP, siRNA knockdown, in vitro transcription assays, xenograft tumor assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complex purification, ChIP, functional knockdown with multiple readouts; replicated by independent labs\",\n      \"pmids\": [\"21502505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"JMJD2B (KDM4B) interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex; it is recruited to ERα target sites where it demethylates H3K9me3 to facilitate transcription of ER-responsive genes including MYB, MYC, and CCND1.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, mammary gland-specific conditional knockout mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, in vivo genetic deletion, replicated independently\",\n      \"pmids\": [\"21445275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HIF-1α directly binds recognition sites in the JMJD2B gene promoter and induces its transcription under hypoxia; ectopically expressed JMJD2B retains histone lysine demethylase activity under hypoxic conditions.\",\n      \"method\": \"ChIP, reporter assay, qRT-PCR, Western blot, ectopic expression with demethylase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct ChIP of HIF-1α at JMJD2B promoter, functional demethylase activity confirmed in hypoxia; replicated by multiple subsequent studies\",\n      \"pmids\": [\"18984585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM4B enzymatic (demethylase) activity is required to enhance androgen receptor (AR) transcriptional activity; independently of demethylase activity, KDM4B enhances AR protein stability by inhibiting AR ubiquitination. Knockdown of KDM4B causes near-complete depletion of AR protein. KDM4B is itself androgen-regulated.\",\n      \"method\": \"siRNA screen, co-immunoprecipitation, ubiquitination assay, luciferase reporter, Western blot\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity mutants tested, ubiquitination assay, multiple cell lines; single lab with orthogonal methods\",\n      \"pmids\": [\"23435229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of KDM4B in ternary complex with pyridine 2,4-dicarboxylic acid and H3K9me3 peptide was solved, revealing the active-site architecture and a selective K9/K36 binding site. Pharmacological and genetic inhibition of KDM4B increased H3K9me3 and silenced growth-related AR-responsive genes.\",\n      \"method\": \"X-ray crystallography, virtual screening, in vitro enzymatic inhibition assay, ChIP, cell viability assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure solved with functional validation by inhibition and mutagenesis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24971742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KDM4B controls expression of ER and FOXA1 genes by demethylating repressive H3K9me3 marks in their upstream regulatory regions, enabling GATA-3 binding. KDM4B physically interacts with GATA-3 in breast cancer cells and co-activates GATA-3 transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter, siRNA knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with functional reporter assay; single lab\",\n      \"pmids\": [\"23723241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Kdm4b is rapidly recruited to DNA double-strand breaks induced by laser micro-irradiation in a PARP1-dependent and demethylase-activity-dependent manner. Overexpression of Kdm4b decreased γH2AX foci 6 hours after γ-irradiation and increased cell survival. H3K9me2/3 levels decreased at early time points after γ-irradiation.\",\n      \"method\": \"Laser micro-irradiation, live-cell imaging (EGFP fusion), PARP inhibitor treatment, γH2AX foci quantification, clonogenic survival assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell recruitment assay, pharmacological dissection of PARP1 dependency, demethylase-dead mutant used; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"23744078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KDM4B promotes osteogenic commitment of MSCs by removing repressive H3K9me3 at DLX gene loci, thereby activating DLX expression. KDM6B acts in parallel on H3K27me3/HOX. Depletion of KDM4B shifts MSCs toward adipogenesis.\",\n      \"method\": \"shRNA knockdown, ChIP, differentiation assays (osteogenic/adipogenic), ovariectomized and aging mouse models\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating H3K9me3 removal at DLX loci, KO phenotype in vivo; replicated in multiple subsequent studies\",\n      \"pmids\": [\"22770241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Jmjd2b and Jmjd2c (KDM4C) are necessary for self-renewal of mouse ESCs and iPS cell generation. Genome-wide occupancy reveals Jmjd2b-unique target sites belong to the Core (Nanog) regulatory module; Jmjd2b and Nanog act through an interconnected regulatory loop.\",\n      \"method\": \"RNAi screen, genome-wide ChIP-seq occupancy, iPS reprogramming assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq combined with functional RNAi screen and iPS assays; rigorous study\",\n      \"pmids\": [\"24361252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Heat shock protein Hsp90 physically interacts with and stabilizes KDM4B protein. Pharmacological Hsp90 inhibition with geldanamycin causes ubiquitin-dependent proteasomal degradation of KDM4B (but not KDM4C). KDM4B is ubiquitinated on lysines 337 and 562; simultaneous K337R/K562R substitution suppresses geldanamycin-induced degradation.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological inhibition (geldanamycin), ubiquitination assay, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP, mutagenesis of ubiquitination sites, pharmacological validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23589305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Histone demethylase Kdm4b acts as a co-factor of C/EBPβ during mitotic clonal expansion (MCE) of 3T3-L1 preadipocytes. Kdm4b expression is induced by C/EBPβ binding to its promoter; Kdm4b interacts with C/EBPβ, is recruited to promoters of C/EBPβ-regulated cell cycle genes (Cdc45l, Mcm3, Gins1, Cdc25c), demethylates H3K9me3 there, and activates their transcription.\",\n      \"method\": \"ChIP-on-chip, EMSA, luciferase assay, co-immunoprecipitation, siRNA knockdown, ChIP\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, Co-IP, EMSA, reporter assay); single lab\",\n      \"pmids\": [\"22722334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p53 directly induces JMJD2B gene expression by binding a canonical p53 consensus motif in the JMJD2B promoter. JMJD2B induction attenuates transcription of p53 targets (p21, PIG3, PUMA) in a catalytic-activity-dependent manner, forming a negative auto-regulatory feedback loop on p53 transcriptional output.\",\n      \"method\": \"ChIP, siRNA knockdown, luciferase reporter, gain/loss-of-function, xenograft tumor assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP of p53 at JMJD2B promoter, catalytic mutant tested; single lab\",\n      \"pmids\": [\"28073943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p53 directly induces JMJD2b expression through promoter binding, leading to reduction of H3K9me3 at pericentric heterochromatin after DNA damage. JMJD2b depletion delays slow-phase HC DNA repair and reduces clonogenic survival after ionizing irradiation.\",\n      \"method\": \"ChIP, siRNA knockdown, IR survival assay, Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP for p53 at JMJD2b promoter; single lab, complementary to PMID 28073943\",\n      \"pmids\": [\"23376847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TGF-β induces KDM4B expression in MSCs; KDM4B is recruited to the SOX9 promoter, removes H3K9me3, and activates SOX9 transcription. KDM4B depletion reduces SMAD3 occupancy at the SOX9 promoter, establishing KDM4B as required for SMAD-dependent coactivation of SOX9 during chondrogenesis.\",\n      \"method\": \"ChIP, shRNA knockdown, overexpression, differentiation assays\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing KDM4B at SOX9 promoter with H3K9me3 removal; single lab\",\n      \"pmids\": [\"26485430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM4B is phosphorylated by protein kinase A (PKA) under castration-resistance–promoting conditions, enabling its binding to splicing factor SF3B3. KDM4B binds RNA near the 5'-CE3 region of AR pre-mRNA, increases chromatin accessibility, and couples the spliceosome to chromatin to promote inclusion of CE3, generating the AR-V7 splice variant.\",\n      \"method\": \"Immunoprecipitation, RNA immunoprecipitation, ATAC-seq, genome-wide splicing profiling, phosphorylation assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, phosphorylation mapping, ATAC-seq, multiple orthogonal methods in single lab establishing novel non-histone function\",\n      \"pmids\": [\"31647098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCF^Fbxo22 ubiquitylates KDM4B complexed with tamoxifen-bound ERα, leading to KDM4B degradation and release of steroid receptor coactivator (SRC) from ER. This Fbxo22-dependent KDM4B degradation is required for tamoxifen antagonist activity; Fbxo22 depletion restores ER-dependent transcription via AF1 even in SERM-treated cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, live-cell fluorescence imaging (FRET/BiFC), ChIP, in vitro and in vivo tumor growth\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical ubiquitination assay, live-cell imaging, ChIP on nearly all ER-SRC-bound enhancers, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"30418174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM4B forms complexes with β-catenin in vitro and in vivo (involving KDM4B amino acids 353–740) and also interacts with TCF4. KDM4B co-occupies β-catenin/TCF4 target gene promoters, and its knockdown reduces expression of JUN, MYC, and Cyclin D1.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo), ChIP, siRNA knockdown, clonogenic assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vitro and in vivo Co-IP with domain mapping, ChIP; single lab\",\n      \"pmids\": [\"24481461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"JMJD2B physically associates with β-catenin and enhances its nuclear localization and transcriptional activity in gastric cancer cells. JMJD2B binds the vimentin promoter together with β-catenin and induces local H3K9 demethylation to activate vimentin transcription, promoting EMT.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, invasion/migration assays, in vivo metastasis\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with functional EMT readouts; single lab\",\n      \"pmids\": [\"24077348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In chick embryo, KDM4B dynamically occupies regulatory regions of the Dlx3 locus and removes H3K9me3 to activate Dlx3 expression; loss of KDM4B causes defective otic vesicle invagination. A catalytically dead KDM4B mutant fails to rescue the invagination phenotype, whereas DLX3 co-electroporation rescues it, placing KDM4B upstream of DLX3 in otic placode invagination.\",\n      \"method\": \"In vivo ChIP, electroporation/knockdown in chick embryo, rescue with catalytic-dead mutant\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vivo ChIP with catalytic dead mutant rescue experiment; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26598618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of KDM4B in MSCs increases H3K9me3 and impairs β-catenin/Smad1-mediated transcription. KDM4B ablation induces senescence-associated heterochromatin foci formation and promotes MSC exhaustion. KDM4B is required for parathyroid hormone-mediated bone anabolic signaling.\",\n      \"method\": \"Conditional knockout mice, ChIP, differentiation assays, senescence assays\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo conditional KO with ChIP and mechanistic pathway dissection; replicated across multiple conditions\",\n      \"pmids\": [\"33571444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4B physically and functionally associates with CCAR1 and MED1 in a complex. This KDM4B-CCAR1-MED1 complex localizes to promoters of osteoclast-related genes upon RANKL stimulation, induces H3K9 demethylation (euchromatinization), and recruits NF-κB p65 via a direct interaction between KDM4B and p65.\",\n      \"method\": \"Co-immunoprecipitation, genome-wide ChIP-seq, conditional KO mice (myeloid-specific), in vivo KDM4B inhibitor treatment\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq, Co-IP, in vivo genetic and pharmacological validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34031372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Inactivation of KDM4B (via H3.3G34R or IDH1/2 mutations) cooperates with ATRX loss to drive Alternative Lengthening of Telomeres (ALT) in glioblastoma. KDM4B overexpression in ALT cancer cells abrogates ALT-associated features, identifying KDM4B as the key demethylase whose inactivation promotes ALT.\",\n      \"method\": \"Mouse ESC genetic KO (ATRX, TP53, TERT, KDM4B), KDM4B overexpression in ALT cells, telomere characterization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue and loss-of-function in multiple models with ALT phenotypic readouts; single lab but rigorous\",\n      \"pmids\": [\"33972520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM4B interacts with eIF2α in the cytoplasm and maintains reduced phosphorylation of eIF2α; this cytoplasmic function is independent of its canonical histone demethylase role but requires demethylase activity. KDM4B depletion or inhibition activates the unfolded protein response (UPR) and causes preferential apoptosis in PTEN-deficient triple-negative breast cancers.\",\n      \"method\": \"Co-immunoprecipitation (cytoplasmic fraction), siRNA/small molecule inhibition, UPR pathway activation assays, apoptosis assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cytoplasmic Co-IP with eIF2α, demethylase-activity dependence tested; single lab\",\n      \"pmids\": [\"30266800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM4B activates LINE-1 retrotransposons by removing H3K9me3 from evolutionarily young LINE-1 elements genome-wide. KDM4B overexpression enhances LINE-1 retrotransposition efficacy, copy number, and associated DNA damage in breast cancer cells.\",\n      \"method\": \"Genome-wide H3K9me3 ChIP-seq, LINE-1 retrotransposition assay, copy number analysis, KDM4B inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with functional retrotransposition assay; single lab\",\n      \"pmids\": [\"30459150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"N-Myc physically interacts with and recruits KDM4B in neuroblastoma cells. KDM4B regulates Myc pathway target genes and neuroblastoma cell proliferation and differentiation in vitro and xenograft growth in vivo.\",\n      \"method\": \"Immunoprecipitation, immunofluorescence, ChIP, shRNA knockdown, xenograft\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP showing N-Myc/KDM4B interaction with ChIP; single lab\",\n      \"pmids\": [\"25925418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD2B activity controls autophagy via epigenetic regulation of LC3B (MAP1LC3B) gene expression; JMJD2B knockdown reduces H3K9 demethylation at the LC3B promoter and decreases autophagy, reducing intracellular amino acid availability under glucose deprivation in colorectal cancer cells.\",\n      \"method\": \"ChIP, siRNA knockdown, metabolic profiling, xenograft, immunofluorescence, electron microscopy\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at LC3B promoter with multiple metabolic and functional assays; single lab\",\n      \"pmids\": [\"32483417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM4B physically interacts with c-Jun and co-occupies the IL-8, MMP1, and ITGAV promoters; demethylase activity is required for KDM4B-mediated upregulation of these targets. KDM4B depletion reduces integrin αV expression and impairs H. pylori-induced cell migration.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, demethylase-dead mutant analysis, siRNA knockdown\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with catalytic-activity dependency; single lab\",\n      \"pmids\": [\"30683841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM4B physically interacts with c-Myc; the KDM4B-c-Myc complex is co-recruited to c-Myc-binding sequences on promoters of metabolic genes (LDHA, ENO1, PFK) and synergistically promotes transactivation of LDHA in a demethylase-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, reporter assay, ChIP, Seahorse metabolic flux analysis, metabolomics\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, and reporter assay with demethylase dependency; single lab\",\n      \"pmids\": [\"34335964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"JMJD2B promotes adipogenesis by removing H3K9me2/3 from the promoters of PPARγ and C/EBPα, activating their expression during 3T3-L1 differentiation.\",\n      \"method\": \"ChIP, siRNA knockdown, overexpression, adipogenesis assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at PPARγ/C/EBPα promoters with gain/loss-of-function; single lab\",\n      \"pmids\": [\"28060835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"JMJD2B removes H3K9me2/3 from the PPARγ2 promoter to activate its expression and downstream lipogenic target genes, promoting hepatic steatosis. JMJD2B interacts with activated LXRα and is recruited to LXR response elements (LXRE), reducing H3K9me2/3 there to activate LXRα-dependent lipogenesis.\",\n      \"method\": \"ChIP, co-immunoprecipitation, adenoviral overexpression, siRNA knockdown, reporter assay, in vivo mouse model\",\n      \"journal\": \"Scientific reports / International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at target promoters, Co-IP with LXRα, in vivo validation; two independent but related studies from same group\",\n      \"pmids\": [\"30214048\", \"33167594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neuron-specific deletion of Jmjd2b in mice causes increased total spine number but decreased mature spines in hippocampal CA1, hyperactive behavior, working memory deficits, and spontaneous epileptic-like seizures, establishing KDM4B as a required epigenetic regulator of functional neural circuit development.\",\n      \"method\": \"Cre-loxP conditional knockout, spine morphology analysis, behavioral testing (open field, maze), EEG\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO with defined morphological and behavioral phenotypes; single lab\",\n      \"pmids\": [\"27023172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JMJD2B is induced by TGF-β2 and EndMT-promoting/hypoxic conditions in endothelial cells; it mediates site-specific H3K9me3 removal at promoters of mesenchymal genes (CNN1) and TGF-β signaling genes (AKT3, SULF1) to drive endothelial-to-mesenchymal transition. Endothelial-specific deletion of JMJD2B in vivo reduces EndMT after myocardial infarction.\",\n      \"method\": \"siRNA knockdown, endothelial-specific conditional KO mice, ChIP, endothelial barrier assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo endothelial-specific KO with ChIP and EndMT phenotype; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32034099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p-ERK phosphorylates JMJD2B at Thr305, Ser352, Ser566, and Thr1065 under glucose deprivation, stabilizing JMJD2B by protecting it from ubiquitination and proteasomal degradation. The interaction between JMJD2B and p-ERK increases under glucose deprivation.\",\n      \"method\": \"Co-immunoprecipitation, immunoprecipitation/Western blot for phosphorylation, ubiquitination assay, cell viability assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation site mapping with Co-IP; single lab\",\n      \"pmids\": [\"28945223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KDM4B interacts with TRAF6 and promotes TRAF6-mediated K63-linked ubiquitination of AKT, leading to AKT activation and upregulation of GLUT1 expression, thereby promoting glucose uptake in colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP, glucose uptake assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay demonstrating KDM4B-TRAF6-AKT axis; single lab\",\n      \"pmids\": [\"31931846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Inducible expression of JMJD2B in mouse ES cells decreased total H3K9me3 by 63%. When these H3K9me3-reduced cells were used as nuclear transfer donors, H3K9me3 was normalized within minutes following fusion with enucleated oocytes, and development into cloned embryos improved by 30%.\",\n      \"method\": \"Inducible transgenic ES cells, nuclear transfer, immunofluorescence, embryo development assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative H3K9me3 reduction and functional nuclear transfer assay; single lab\",\n      \"pmids\": [\"23263990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KDM4B interacts with MyoD in C2C12 myoblast cells, is recruited to MyoD and myogenin promoters, and demethylates H3K9me3 there, activating their transcription. Depletion of KDM4B inhibits myogenic differentiation, which is rescued by exogenous MyoD.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, shRNA knockdown, luciferase reporter, overexpression rescue\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with rescue experiment; single lab\",\n      \"pmids\": [\"25534856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"JMJD2B/KDM4B forms a protein complex with AP-2 family transcription factor TFAP2C and histone demethylase LSD1 in trophoblast stem cells. This complex predominantly occupies active gene promoters. JMJD2B is also associated with loss of H3K36me3 at a subset of embryonic lineage genes marked by H3K9me3 for stable repression.\",\n      \"method\": \"ChIP-seq, transcriptome analysis, co-immunoprecipitation, siRNA knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with Co-IP identifying JMJD2B-TFAP2C-LSD1 complex; single lab\",\n      \"pmids\": [\"33441614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HIF1α transcriptionally activates WTAP, a component of the m6A methyltransferase complex, which in turn increases m6A modification on KDM4B mRNA, stabilizing it. This establishes a HIF1α→WTAP→m6A-KDM4B axis coupling RNA methylation to histone demethylation (H3K9me3) in AML.\",\n      \"method\": \"ChIP, m6A-seq, mRNA stability assay, siRNA/shRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A-seq and mRNA stability assay linking WTAP to KDM4B mRNA; single lab with mechanistic pathway\",\n      \"pmids\": [\"37087529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The deubiquitinase UCHL1 mediates deubiquitination of KDM4B, stabilizing its protein levels. KDM4B binds directly to the VEGFA promoter, removes H3K9me3, and cooperates with HIF2α to activate VEGFA transcription, promoting angiogenesis and bevacizumab resistance in clear cell renal cell carcinoma.\",\n      \"method\": \"In vivo ubiquitination assay, co-immunoprecipitation, ChIP, luciferase reporter, UCHL1 C90A catalytic mutant\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay with catalytic mutant, ChIP at VEGFA promoter; single lab\",\n      \"pmids\": [\"38743986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM3A and KDM4B co-operate in an auto-regulatory loop in ERα-positive breast cancer; KDM3A primes chromatin for FOXA1 and ER-complex recruitment prior to ER binding. Combined depletion of KDM3A and KDM4B has a greater inhibitory effect on ER activity and cell growth than either alone.\",\n      \"method\": \"ChIP, siRNA knockdown (individual and combined), global gene expression analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP time-course, combined KD functional assay; single lab\",\n      \"pmids\": [\"31390833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Full-length JMJD2b-GFP localizes to chromocenters in a manner dependent on SUV39h (its substrate-generating methyltransferase); in SUV39h-deficient cells, chromocenter localization is reduced alongside global H3K9me3 decrease. PHD Zn-finger and Tudor domains of JMJD2b are required for correct chromocenter localization. FRAP reveals ~50% mobile fraction with <1 s recovery; SUV39h deficiency increases the mobile fraction.\",\n      \"method\": \"GFP fusion live-cell imaging, FRAP, SUV39h knockout cells, truncation/point-mutation analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP with domain-deletion mutants in isogenic genetic backgrounds; single lab\",\n      \"pmids\": [\"21073875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KDM4B is recruited to the ICAM1 and VCAM1 promoters upon TNF-α stimulation, removes H3K9me2, and is required for TNF-α-induced upregulation of these vascular adhesion molecules and subsequent leukocyte adhesion/transmigration in brain microvascular endothelial cells.\",\n      \"method\": \"ChIP, siRNA knockdown, KDM4 inhibitor (ML324), leukocyte adhesion/transmigration assay, in vivo neutrophil adhesion\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at ICAM1/VCAM1 with siRNA and pharmacological inhibition; single lab\",\n      \"pmids\": [\"28327608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"JMJD2B depletion causes spontaneous DNA double-strand breaks and radiosensitizes colorectal cancer cells through suppression of STAT3 signaling; STAT3 overexpression in KDM4B-knockdown cells attenuates DNA damage and restores cell survival. CREB transcription factor directly binds the KDM4B promoter to drive its expression.\",\n      \"method\": \"ChIP, siRNA knockdown/overexpression, γH2AX foci, STAT3 pathway western blot, clonogenic assay\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP for CREB at KDM4B promoter and epistasis via STAT3 OE; single lab, limited mechanistic depth\",\n      \"pmids\": [\"29633065\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM4B (JMJD2B) is a Jumonji-C domain histone lysine demethylase that primarily removes H3K9me3/me2 (and to a lesser extent H3K36me3) to activate gene transcription; it is induced by HIF-1α under hypoxia and by steroid hormones (estrogen, androgen), forms functional complexes with ERα/MLL2, AR, C/EBPβ, c-Jun, c-Myc, N-Myc, NF-κB p65, GATA-3, and MyoD at target gene promoters, and is regulated post-translationally by Hsp90-dependent stabilization, SCF^Fbxo22-mediated ubiquitination/degradation, ERK-mediated phosphorylation, and UCHL1-mediated deubiquitination; it additionally functions as a DNA damage response protein recruited to double-strand breaks in a PARP1-dependent manner, and acts non-canonically as a PKA-phosphorylated splicing scaffold that promotes AR-V7 generation and as a cytoplasmic regulator of eIF2α phosphorylation to control the unfolded protein response.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KDM4B (JMJD2B) is a Jumonji-C domain histone lysine demethylase that actively removes repressive H3K9me3/me2 (and H3K36 methylation) at pericentric heterochromatin and gene-regulatory regions to control chromatin state and transcription [#0, #41]. Its catalytic architecture and K9/K36 selectivity were defined by a ternary crystal structure with H3K9me3 peptide and a 2,4-PDCA inhibitor [#5]. Chromocenter targeting depends on its PHD and Tudor domains and on the substrate-generating methyltransferase SUV39h, coupling its localization to the H3K9me3 mark it erases [#41]. Functionally, KDM4B acts as a transcriptional coactivator that demethylates H3K9me3 at promoters and enhancers bound by lineage and signal-responsive transcription factors, and at ER\\u03b1 target genes its H3K9 demethylation is a prerequisite for MLL2-mediated H3K4 methylation, enforcing mutual exclusivity of the two marks [#1, #2]. Across cell types it partners with sequence-specific factors\\u2014ER\\u03b1, AR, GATA-3, C/EBP\\u03b2, MyoD, c-Jun, c-Myc/N-Myc, NF-\\u03baB p65, \\u03b2-catenin/TCF4, and TFAP2C/LSD1\\u2014to derepress target loci, driving programs from steroid-responsive growth to mesenchymal/skeletal differentiation [#6, #11, #17, #21, #25, #36, #37]. KDM4B is itself an induced effector node: HIF-1\\u03b1, p53, and steroid receptors transcriptionally activate it [#3, #12, #4], while its protein stability is set by Hsp90 binding, SCF^Fbxo22 ubiquitination, ERK phosphorylation, and UCHL1 deubiquitination [#10, #16, #33, #39]. In stem and progenitor cells it sustains ESC self-renewal within the Nanog regulatory module and directs mesenchymal stem cell fate toward osteo/chondrogenesis via H3K9me3 removal at DLX and SOX9 loci [#9, #8, #14, #20]. KDM4B also has non-canonical activities: PARP1-dependent recruitment to double-strand breaks promoting heterochromatin repair [#7], a PKA-phosphorylated splicing-scaffold role coupling the spliceosome to chromatin to generate AR-V7 [#15], and a cytoplasmic interaction with eIF2\\u03b1 that restrains the unfolded protein response [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that KDM4B is a bona fide enzyme that actively removes H3K9me3 in living cells, defining its core catalytic function before downstream biology could be assigned.\",\n      \"evidence\": \"Inducible Jmjd2b-GFP lines with SILAC heavy-methyl metabolic labeling and immunofluorescence at pericentric heterochromatin\",\n      \"pmids\": [\"16738407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Poor in vitro activity left the physiological substrate kinetics unresolved\", \"Did not address gene-specific transcriptional consequences\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified KDM4B as a direct HIF-1\\u03b1 transcriptional target, placing the demethylase downstream of hypoxic signaling.\",\n      \"evidence\": \"ChIP of HIF-1\\u03b1 at the JMJD2B promoter, reporter assays, and demethylase activity confirmation under hypoxia\",\n      \"pmids\": [\"18984585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream genes regulated by hypoxia-induced KDM4B not mapped here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined how KDM4B finds its substrate, showing localization depends on its reader domains and on SUV39h-generated H3K9me3.\",\n      \"evidence\": \"GFP-fusion live-cell imaging, FRAP, and truncation/point mutants in SUV39h-deficient cells\",\n      \"pmids\": [\"21073875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether reader-domain mutants disrupt catalytic turnover\", \"Mobility measured only at chromocenters\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected H3K9me3 removal to specific differentiation programs, showing KDM4B activates DLX (osteogenesis), adipogenic, and cell-cycle gene loci as a transcription-factor cofactor.\",\n      \"evidence\": \"ChIP, Co-IP, EMSA, reporter assays and in vivo ovariectomized/aging mouse models in MSCs and 3T3-L1 cells\",\n      \"pmids\": [\"22770241\", \"22722334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of recruitment to individual TF complexes not fully separated from genome-wide effects\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed KDM4B as a multi-functional transcriptional coactivator across nuclear-receptor and lineage pathways and a DNA-damage-response factor, including a catalysis-independent role in stabilizing AR protein.\",\n      \"evidence\": \"Co-IP, ChIP, ubiquitination assays, demethylase-dead mutants, laser micro-irradiation with PARP inhibition (ER\\u03b1/MLL2, AR, GATA-3, \\u03b2-catenin, DSB systems)\",\n      \"pmids\": [\"21502505\", \"21445275\", \"23435229\", \"23723241\", \"23744078\", \"24077348\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the H3K4/H3K9 mark coordination is direct or sequential at single loci not resolved\", \"Catalysis-independent AR stabilization mechanism (E3 ligase blocked) not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed KDM4B in a p53 feedback circuit, linking the demethylase both to attenuation of p53 transcriptional output and to heterochromatin repair after DNA damage.\",\n      \"evidence\": \"ChIP of p53 at the JMJD2B promoter, siRNA, reporters, IR survival assays\",\n      \"pmids\": [\"28073943\", \"23376847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies; physiological context of the p53\\u2013KDM4B loop in normal tissue unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed KDM4B is required for pluripotency and reprogramming, integrating it into the core Nanog regulatory network.\",\n      \"evidence\": \"RNAi screen, genome-wide ChIP-seq occupancy, and iPS reprogramming assays in mouse ESCs\",\n      \"pmids\": [\"24361252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degree of functional redundancy with KDM4C not fully partitioned\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Solved the catalytic architecture, providing a structural basis for K9/K36 selectivity and a template for inhibitor design.\",\n      \"evidence\": \"X-ray crystallography of the KDM4B/2,4-PDCA/H3K9me3 ternary complex with inhibition and ChIP validation\",\n      \"pmids\": [\"24971742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length enzyme with reader domains not determined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the Hsp90 chaperone and \\u03b2-catenin/MyoD interactions, defining post-translational stabilization and additional lineage-specific coactivator roles.\",\n      \"evidence\": \"Co-IP, ubiquitination-site mutagenesis (K337/K562), geldanamycin treatment, domain mapping, ChIP and rescue in myoblasts\",\n      \"pmids\": [\"23589305\", \"24481461\", \"25534856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The cognate E3 ligase for basal/geldanamycin-induced ubiquitination not identified here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered non-canonical cytoplasmic and degradation-control functions: restraint of eIF2\\u03b1 phosphorylation/UPR and SCF^Fbxo22-dependent degradation that underlies tamoxifen antagonism.\",\n      \"evidence\": \"Cytoplasmic Co-IP with eIF2\\u03b1, UPR/apoptosis assays, ubiquitination assays, live-cell FRET/BiFC and ChIP in ER\\u03b1 systems\",\n      \"pmids\": [\"30266800\", \"30418174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How demethylase activity is required for a cytoplasmic eIF2\\u03b1 function is mechanistically unexplained\", \"Substrate(s) bridging KDM4B to Fbxo22 recognition not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a chromatin-coupled splicing scaffold activity, showing PKA-phosphorylated KDM4B binds SF3B3 and AR pre-mRNA to generate the AR-V7 variant driving castration resistance.\",\n      \"evidence\": \"IP, RIP, ATAC-seq, genome-wide splicing profiling and phosphorylation mapping\",\n      \"pmids\": [\"31647098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of the splicing-scaffold role beyond AR not tested\", \"Relationship between this activity and demethylase catalysis unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended KDM4B into telomere maintenance and bone remodeling, showing its inactivation drives ALT and its complex with CCAR1/MED1 recruits NF-\\u03baB p65 for osteoclastogenesis.\",\n      \"evidence\": \"Genetic KO/overexpression in ESC and ALT models; ChIP-seq, Co-IP, myeloid conditional KO and inhibitor treatment\",\n      \"pmids\": [\"33972520\", \"34031372\", \"33571444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between KDM4B loss and the ALT recombination machinery not delineated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Completed the regulatory loop around KDM4B stability and angiogenic output, adding UCHL1 deubiquitination and an m6A/WTAP mRNA-stabilization axis upstream, with VEGFA/HIF2\\u03b1 downstream.\",\n      \"evidence\": \"Ubiquitination assays with UCHL1 catalytic mutant, m6A-seq, mRNA stability assays, ChIP at VEGFA promoter, xenografts\",\n      \"pmids\": [\"38743986\", \"37087529\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies; interplay of competing stabilizing/destabilizing inputs not integrated quantitatively\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KDM4B's distinct activities\\u2014nuclear demethylase, DSB-repair factor, cytoplasmic eIF2\\u03b1 regulator, and splicing scaffold\\u2014are selected in a given cell state, and which inputs dominate its competing stabilization/degradation pathways, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model integrating catalytic and non-catalytic functions\", \"Determinants of nuclear vs cytoplasmic partitioning unknown\", \"Quantitative hierarchy among Hsp90/Fbxo22/ERK/UCHL1/m6A regulation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 7]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 11, 36]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [41]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 41]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 41]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 14, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 9, 19, 36]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"complexes\": [\n      \"MLL2 H3K4 methyltransferase complex\",\n      \"KDM4B-CCAR1-MED1 complex\",\n      \"JMJD2B-TFAP2C-LSD1 complex\"\n    ],\n    \"partners\": [\n      \"ESR1\",\n      \"AR\",\n      \"GATA3\",\n      \"CEBPB\",\n      \"CTNNB1\",\n      \"MYOD1\",\n      \"HSP90\",\n      \"EIF2AK\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}