{"gene":"KDM7A","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2010,"finding":"KDM7A (KIAA1718) is a dual-specificity histone demethylase that removes di-methyl marks from both H3K9me2 and H3K27me2, and promotes neural differentiation through direct transcriptional activation of FGF4 by removing these repressive marks; catalytically inactive mutant fails to rescue neural differentiation knockdown phenotype.","method":"In vitro demethylase assay, catalytically inactive mutant rescue experiments, mouse embryonic stem cell knockdown/overexpression, RT-PCR","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic activity demonstrated, catalytic dead mutant used as control, multiple orthogonal methods, replicated in chick embryo model","pmids":["20084082"],"is_preprint":false},{"year":2010,"finding":"KDM7A is predominantly expressed in epiblast cells of the primitive streak in early chick embryos, and its overexpression expands the neural plate while knockdown impairs neural plate formation; co-electroporation of Fgf4 rescues the KDM7A knockdown neural induction defect, placing KDM7A upstream of FGF4 in neural induction.","method":"In vivo chick embryo electroporation, knockdown/overexpression, genetic epistasis rescue with Fgf4","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with rescue experiment, consistent with mechanistic findings from PMID:20084082","pmids":["20981832"],"is_preprint":false},{"year":2011,"finding":"KDM7A (JHDM1D) suppresses tumor angiogenesis under nutrient starvation by downregulating expression of multiple angiogenic factors (VEGF-B, angiopoietins) in cancer cells, leading to reduced CD31+ blood vessel formation and CD11b+ macrophage infiltration in tumor xenografts.","method":"Stable cDNA expression and siRNA silencing in B16 and HeLa cells, in vivo xenograft tumor growth assays, immunohistochemistry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — clean gain/loss-of-function with defined in vivo phenotype, but mechanism linking demethylase activity to angiogenic factor regulation not dissected","pmids":["22143793"],"is_preprint":false},{"year":2015,"finding":"G9a promotes H3K27 methylation at the E-cadherin promoter partly by downregulating KDM7A; overexpression of KDM7A elevates E-cadherin expression in gemcitabine-resistant PANC-1-R cells, while knockdown of KDM7A downregulates E-cadherin in PANC-1 cells, placing KDM7A as an antagonist of G9a-mediated H3K27 methylation.","method":"Overexpression and knockdown in PANC-1 pancreatic cancer cells, ChIP, Western blot for histone marks and E-cadherin","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — epistasis defined through gain/loss-of-function and ChIP, single lab","pmids":["26688070"],"is_preprint":false},{"year":2016,"finding":"KDM7A regulates TNF-α-induced ICAM1 protein upregulation via a lysosome-dependent pathway (not epigenetic/transcriptional): KDM7A knockdown reduces ICAM1 protein stability and promotes lysosomal degradation of ICAM1 by increasing TFEB-mediated lysosomal activity, without affecting ICAM1 mRNA levels.","method":"siRNA knockdown, cycloheximide chase, lysosome and proteasome inhibitor treatment, immunocytochemistry, Western blot in human brain microvascular endothelial cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal approaches (cycloheximide, inhibitors, immunocytochemistry) in single lab identifying a non-canonical post-translational mechanism","pmids":["27565733"],"is_preprint":false},{"year":2018,"finding":"KDM7A binds to AR target-gene promoters upon androgen stimulation (ChIP), demethylates H3K27me2 at those promoters, and is required for androgen receptor-driven downstream gene expression and proliferation in prostate cancer cells.","method":"Stable shRNA knockdown in LNCaP cells, ChIP, Western blot for H3K27me2, AR target gene expression assays, xenograft tumor growth","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal ChIP and functional knockdown with defined phenotype in single lab","pmids":["30183076"],"is_preprint":false},{"year":2019,"finding":"KDM7A directly binds to the promoters of C/EBPα and Sfrp1 (by ChIP), removes H3K9me2 and H3K27me2 marks, and promotes adipogenic over osteogenic differentiation in mesenchymal progenitor cells; enzymatic activity is required since a demethylase-dead point mutant fails to alter differentiation.","method":"ChIP assay, knockdown/overexpression with catalytic dead mutant in ST2 stromal cells and primary marrow stromal cells, adipogenic/osteogenic differentiation assays","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP demonstrating direct promoter binding plus catalytic dead mutant controls, multiple orthogonal methods, single lab","pmids":["30614617"],"is_preprint":false},{"year":2019,"finding":"KDM7A is required for breast cancer stem cell (BCSC) maintenance by epigenetically upregulating stemness factors KLF4 and c-MYC, and inhibits apoptosis by upregulating BCL2; restoring BCL2 expression rescues apoptosis in KDM7A-knockdown cells, placing KDM7A upstream of BCL2-mediated apoptotic inhibition.","method":"siRNA knockdown, overexpression rescue, mammosphere formation assay, in vivo tumor growth, Western blot for BCL2/BAD phosphorylation","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2–3 — defined cellular phenotype with rescue experiment, mechanistic link to BCL2 established by re-expression, single lab","pmids":["31236965"],"is_preprint":false},{"year":2019,"finding":"KDM7A knockdown in porcine embryos increases H3K9me1/2 and H3K27me1/2 global levels, reduces blastocyst formation, reduces ICM/total cell ratio, and alters expression of pluripotency genes (NANOG, OCT4) and other KDMs, establishing KDM7A as required for early embryo development and first cell lineage specification.","method":"mRNA knockdown in porcine IVF/PA/SCNT embryos, immunofluorescence for histone marks, RT-PCR for pluripotency/KDM gene expression","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with multiple orthogonal readouts (IF for histone marks, gene expression, blastocyst rates), single lab","pmids":["31216927"],"is_preprint":false},{"year":2021,"finding":"MKL1 physically interacts with and recruits KDM7A to the RHOJ promoter to cooperatively remove H3K9/H3K27 methylation, enabling TGF-β-induced RHOJ transcription and breast cancer cell migration/invasion; TGF-β induces KDM7A transcription via a SMAD2/SMAD4 complex binding to the KDM7A promoter.","method":"Co-immunoprecipitation (MKL1-KDM7A interaction), ChIP (KDM7A and histone marks at RHOJ promoter), siRNA knockdown, in vitro migration/invasion assays, in vivo xenograft, ChIP for SMAD2/SMAD4 at KDM7A promoter","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP for interaction, ChIP for promoter binding and histone marks, multiple functional readouts, single lab with multiple orthogonal methods","pmids":["34249916"],"is_preprint":false},{"year":2021,"finding":"KDM7A overexpression in hepatocytes upregulates DGAT2 by removing H3K9me2 and H3K27me2 from the DGAT2 promoter (ChIP), leading to increased triglyceride accumulation and hepatic steatosis; adenovirus-mediated KDM7A overexpression in mice reproduces hepatic steatosis in vivo.","method":"KDM7A overexpression/knockdown in AML12 cells, ChIP for H3K9me2/H3K27me2 at DGAT2 promoter, adenoviral overexpression in mice, triglyceride quantification","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP mechanistically links demethylase activity to DGAT2 promoter, in vivo validation, single lab","pmids":["34681759"],"is_preprint":false},{"year":2023,"finding":"KDM7A/B demethylases regulate H3K79 methylation in chondrocytes; individual siRNA silencing of KDM7A or KDM7B in human chondrocytes increases H3K79me and glycosaminoglycan content, and intra-articular daminozide (KDM2/7 inhibitor) protects against osteoarthritis in a mouse DMM model.","method":"Individual siRNA silencing of KDM7A/B, Western blot and immunofluorescence for H3K79me, Alcian blue staining, in vivo DMM mouse model with intra-articular injection","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2 — individual gene silencing with defined epigenetic and functional readouts, in vivo validation, but combined with pharmacological inhibitor targeting both KDM7A and KDM7B","pmids":["36927643"],"is_preprint":false},{"year":2023,"finding":"KDM7A knockdown in N2A neuronal cells and mouse hippocampal dentate gyrus neurons reduces H3K9me1/2 and H3K27me1/2 enrichment near transcription start sites and markedly decreases expression of immediate early genes (IEGs); in vivo Kdm7a knockdown via AAV impairs hippocampal c-Fos expression, neuronal activity, emotion, and memory in mice.","method":"CUT&Tag-seq (histone marks), RNA-seq, AAV-mediated in vivo knockdown, behavioral assays in mice, immunofluorescence","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 — genome-wide CUT&Tag and RNA-seq combined with in vivo AAV knockdown and behavior, multiple orthogonal methods","pmids":["37565374"],"is_preprint":false},{"year":2024,"finding":"KDM7A removes H3K9me2 and H3K27me2 from the Fap (fibroblast activation protein α) and Rankl promoters in osteoprogenitor cells, upregulating FAP and RANKL expression; conditional Kdm7a deletion in osterix+ cells in mice increases cancellous bone mass, enhances osteoblast differentiation, reduces osteoclast differentiation, and protects against ovariectomy-induced bone loss.","method":"Conditional knockout mouse (osterix-Cre), ChIP for H3K9me2/H3K27me2 at Fap and Rankl promoters, bone histomorphometry, co-culture of BMSCs with osteoclast precursors, recombinant FAP rescue","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 — conditional KO with in vivo phenotype, ChIP identifying direct promoter targets, rescue with recombinant FAP, multiple orthogonal methods","pmids":["38346941"],"is_preprint":false},{"year":2024,"finding":"KDM7A knockdown in mPFC neurons reduces H3K9me2 and H3K27me2 enrichment at the Fscn1 promoter, decreasing Fscn1 expression, dendritic spine density, and neuronal activity, leading to impaired morphine-conditioned place preference memory consolidation.","method":"AAV-mediated Kdm7a knockdown in mouse mPFC, Nanopore direct RNA sequencing, ChIP for H3K9me2/H3K27me2 at Fscn1 promoter, behavioral CPP assay, dendritic spine imaging","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 — in vivo AAV knockdown, ChIP, transcriptomics, and behavioral assays providing multiple orthogonal lines of evidence","pmids":["39836528"],"is_preprint":false},{"year":2024,"finding":"Nuclear miR-451a activates KDM7A transcription by interacting with an enhancer region in the KDM7A locus in an AGO2-dependent manner, leading to increased KDM7A expression and cetuximab resistance in head and neck squamous cell carcinoma.","method":"Small RNA sequencing, FISH for nuclear miR-451a localization, ChIRP (chromatin isolation by RNA purification), siRNA knockdown, microarray analysis","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIRP for RNA-chromatin interaction plus functional knockdown, but mechanism linking KDM7A upregulation to cetuximab resistance is not fully dissected at the enzymatic level","pmids":["38943031"],"is_preprint":false},{"year":2024,"finding":"A KDM7A inhibitor (compound 4) blocks KDM7A binding to H3K27me3, reduces MKRN1 transcription (identifying MKRN1 as a downstream target of KDM7A), and increases cell cycle inhibitors p16, p21, p27 while reducing breast cancer stem cell markers in triple-negative breast cancer cells.","method":"Structure-based virtual screening, in vitro demethylase inhibition assay, ChIP (KDM7A binding to H3K27me3), gene expression analysis, cell cycle assay","journal":"Bioorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — in vitro demethylase activity inhibition and ChIP evidence for target gene regulation, single lab","pmids":["39509788"],"is_preprint":false},{"year":2023,"finding":"KDM7A interacts with covalently closed circular DNA (cccDNA) of HBV to promote HBV replication, and also downregulates the IFN-γ/JAK2/STAT1 signaling pathway in macrophages and hepatocytes.","method":"Described as mechanistic study (specific methods not detailed in abstract; interaction with cccDNA and signaling pathway downregulation reported)","journal":"Microbiology spectrum","confidence":"Low","confidence_rationale":"Tier 3 — limited methodological detail in abstract, single report","pmids":["37623314"],"is_preprint":false},{"year":2026,"finding":"KDM7A suppresses profibrotic macrophage (Fib-Mac) polarization by maintaining H3K27me2 at the TLR8 enhancer to promote TLR8 expression; Kdm7a knockout in mice expands Fib-Mac populations and exacerbates bleomycin-induced lung fibrosis.","method":"Kdm7a conditional knockout mice, single-cell RNA sequencing, bleomycin lung fibrosis model, ChIP/epigenetic analysis at TLR8 enhancer","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO phenotype with scRNA-seq and epigenetic mechanistic data at TLR8 enhancer, single lab","pmids":["41578150"],"is_preprint":false},{"year":2023,"finding":"Kdm7a overexpression in Xenopus does not affect early neural/eye-field specification genes but alters retinal neuronal subtype distribution in the mature retina, disfavoring ganglion cells and promoting horizontal cells, suggesting a role in the timing of retinal neurogenesis.","method":"Xenopus overexpression (ortholog study), retinal cell subtype quantification, in situ hybridization for kdm7a expression pattern","journal":"Developmental dynamics","confidence":"Low","confidence_rationale":"Tier 3 — overexpression in Xenopus ortholog without mechanistic dissection of demethylase targets; phenotype described without pathway placement","pmids":["37909656"],"is_preprint":false}],"current_model":"KDM7A is a dual-specificity histone demethylase that removes mono- and di-methyl marks from H3K9 (me1/2) and H3K27 (me1/2) to activate transcription of target genes; it regulates neural differentiation via FGF4, adipogenic/osteogenic lineage balance via C/EBPα and Sfrp1/Wnt signaling, androgen receptor-driven gene expression in prostate cancer, hepatic lipid metabolism via DGAT2, neuronal immediate early genes and reward memory via Fscn1, and bone homeostasis via FAP and RANKL, while also acting through non-canonical mechanisms such as lysosome-mediated ICAM1 protein stabilization, and its transcription is regulated upstream by TGF-β/SMAD2/SMAD4 and nuclear miR-451a/AGO2."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing that KDM7A possesses intrinsic dual-specificity demethylase activity toward H3K9me2 and H3K27me2 resolved the enzymatic identity of this JmjC-domain protein and linked it to neural differentiation via FGF4 transcriptional activation.","evidence":"In vitro demethylase assay with catalytic-dead mutant control, mouse ESC knockdown/overexpression, and chick embryo electroporation with FGF4 epistasis rescue","pmids":["20084082","20981832"],"confidence":"High","gaps":["Structural basis for dual H3K9/H3K27 substrate recognition not determined","Whether H3K9me1 and H3K27me1 are also substrates was not systematically tested in vitro at this stage","Upstream signals controlling KDM7A during neural induction were unknown"]},{"year":2011,"claim":"Demonstrating that KDM7A suppresses tumor angiogenesis under nutrient stress expanded its biology beyond development, though the direct chromatin targets mediating angiogenic factor downregulation remained undefined.","evidence":"Stable overexpression/siRNA in cancer cells, xenograft assays with immunohistochemistry for CD31 and CD11b","pmids":["22143793"],"confidence":"Medium","gaps":["No ChIP evidence identifying direct promoter targets of KDM7A at angiogenic factor loci","Catalytic-dead mutant not tested, so demethylase-dependence not confirmed","Single lab without independent replication"]},{"year":2016,"claim":"Discovery that KDM7A regulates ICAM1 protein stability through lysosomal degradation (TFEB pathway) without affecting ICAM1 mRNA revealed a non-canonical, non-epigenetic function for this demethylase.","evidence":"siRNA knockdown in brain microvascular endothelial cells, cycloheximide chase, lysosome/proteasome inhibitors","pmids":["27565733"],"confidence":"Medium","gaps":["Whether this non-epigenetic function requires demethylase catalytic activity is unknown","Direct physical interaction between KDM7A and TFEB or lysosomal machinery not shown","Not independently replicated"]},{"year":2018,"claim":"Showing that KDM7A is recruited to androgen receptor target-gene promoters upon androgen stimulation to remove H3K27me2 established KDM7A as a hormone-responsive transcriptional coactivator in prostate cancer.","evidence":"shRNA knockdown in LNCaP cells, ChIP for KDM7A and H3K27me2 at AR target promoters, xenograft growth","pmids":["30183076"],"confidence":"Medium","gaps":["Direct physical interaction between KDM7A and AR not demonstrated","Whether H3K9me2 demethylation also occurs at AR target loci was not addressed","Single lab"]},{"year":2019,"claim":"ChIP-based identification of C/EBPα and Sfrp1 promoters as direct KDM7A targets—together with catalytic-dead mutant failure to drive adipogenesis—established that enzymatic H3K9me2/H3K27me2 demethylation controls mesenchymal lineage commitment between adipogenic and osteogenic fates.","evidence":"ChIP, overexpression/knockdown with catalytic-dead mutant in ST2 and primary marrow stromal cells, differentiation assays","pmids":["30614617"],"confidence":"High","gaps":["In vivo bone/fat phenotype from conditional knockout not yet reported at this time","Whether KDM7A acts downstream of specific signaling cues in marrow was not identified"]},{"year":2019,"claim":"KDM7A knockdown in porcine embryos increased global H3K9me1/2 and H3K27me1/2 and impaired blastocyst formation, establishing that KDM7A-dependent demethylation is necessary for early embryonic development and first lineage specification.","evidence":"mRNA knockdown in IVF/PA/SCNT porcine embryos, immunofluorescence, RT-PCR for pluripotency genes","pmids":["31216927"],"confidence":"Medium","gaps":["Specific promoter targets in early embryos not identified by ChIP","Rescue with wild-type or catalytic-dead KDM7A not performed","Porcine system; relevance to human embryogenesis not directly tested"]},{"year":2021,"claim":"Identification of MKL1 as a physical partner that recruits KDM7A to the RHOJ promoter, and of SMAD2/SMAD4 as direct transcriptional activators of KDM7A itself, placed KDM7A within TGF-β signaling and explained how its expression and chromatin targeting are regulated during cancer cell invasion.","evidence":"Co-immunoprecipitation, ChIP at RHOJ and KDM7A promoters, knockdown, xenograft assays","pmids":["34249916"],"confidence":"High","gaps":["Whether MKL1-KDM7A interaction is direct or bridged was not resolved","Genome-wide scope of MKL1-KDM7A co-occupancy not mapped"]},{"year":2021,"claim":"ChIP evidence that KDM7A removes H3K9me2/H3K27me2 at the DGAT2 promoter to drive triglyceride accumulation linked the demethylase to hepatic lipid metabolism and steatosis in vivo.","evidence":"Overexpression/knockdown in AML12 cells, ChIP at DGAT2 promoter, adenoviral overexpression in mouse liver","pmids":["34681759"],"confidence":"Medium","gaps":["Catalytic-dead mutant not tested in the hepatocyte system","Conditional hepatocyte knockout not generated","Upstream signals inducing KDM7A in steatotic conditions not identified"]},{"year":2023,"claim":"Genome-wide CUT&Tag and RNA-seq in neurons combined with in vivo AAV knockdown showed that KDM7A maintains H3K9me1/2 and H3K27me1/2 at TSS regions and is essential for immediate-early gene expression, neuronal activity, and memory, establishing a CNS-specific functional role.","evidence":"CUT&Tag-seq, RNA-seq in N2A cells, AAV-mediated hippocampal knockdown in mice, behavioral assays","pmids":["37565374"],"confidence":"High","gaps":["Direct promoter targets among IEGs not validated by individual ChIP","Cell-type specificity within hippocampal subpopulations not resolved","Whether catalytic activity is required for IEG regulation was not tested with mutant"]},{"year":2024,"claim":"Conditional deletion of Kdm7a in osterix+ osteoprogenitors increased bone mass and protected against ovariectomy-induced bone loss by reducing FAP and RANKL at the promoter level, providing definitive in vivo genetic evidence for KDM7A in bone homeostasis.","evidence":"Osterix-Cre conditional knockout, ChIP at Fap/Rankl promoters, bone histomorphometry, recombinant FAP rescue, co-culture assays","pmids":["38346941"],"confidence":"High","gaps":["Therapeutic targeting of KDM7A in osteoporosis not tested with specific inhibitors","Whether KDM7A also regulates osteoclast-intrinsic programs is unknown"]},{"year":2024,"claim":"Identification of Fscn1 as a direct KDM7A target in mPFC neurons linked the demethylase to dendritic spine remodeling and reward memory consolidation, extending its neuronal role beyond hippocampal IEGs.","evidence":"AAV knockdown in mouse mPFC, Nanopore RNA-seq, ChIP at Fscn1 promoter, dendritic spine imaging, conditioned place preference","pmids":["39836528"],"confidence":"High","gaps":["Whether KDM7A-Fscn1 axis generalizes to other forms of memory not tested","Catalytic-dead rescue not performed in this brain region"]},{"year":2024,"claim":"Nuclear miR-451a was found to activate KDM7A transcription via enhancer interaction in an AGO2-dependent manner, revealing a non-canonical RNA-mediated mechanism of KDM7A gene regulation beyond the previously known SMAD-dependent pathway.","evidence":"ChIRP, small RNA sequencing, FISH, siRNA knockdown in HNSCC cells","pmids":["38943031"],"confidence":"Medium","gaps":["Whether miR-451a/AGO2 mechanism operates in non-cancer contexts is unknown","Direct causal link between KDM7A upregulation and cetuximab resistance not fully dissected at the epigenetic level"]},{"year":null,"claim":"Key unresolved questions include the structural basis for KDM7A's dual H3K9/H3K27 substrate specificity, the full repertoire of its non-epigenetic functions, and whether selective KDM7A inhibitors can be developed for therapeutic applications in bone loss, neurological disorders, or cancer.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of KDM7A in complex with nucleosomal substrates","Mechanism of the non-canonical lysosomal/TFEB-related function remains unresolved","Genome-wide mapping of KDM7A chromatin occupancy across tissues is lacking","No selective KDM7A inhibitor with validated in vivo pharmacokinetics"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,6,8,12,13,14]},{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,6,10,13]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,5,6,10,13,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,6,9,10,13,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,6,9,10,13,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,5,6,8,9,10,12,13,14]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,5,6,10,12,13,14]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,5,6,8,10,12,13,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,6,9,10,13,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,6,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,15]}],"complexes":[],"partners":["MKL1","SMAD2","SMAD4","AGO2","AR"],"other_free_text":[]},"mechanistic_narrative":"KDM7A is a dual-specificity JmjC-domain histone demethylase that removes mono- and di-methyl marks from H3K9 and H3K27, thereby relieving transcriptional repression at target gene promoters to regulate neural differentiation, mesenchymal lineage commitment, bone homeostasis, hepatic lipid metabolism, and neuronal immediate-early gene expression [PMID:20084082, PMID:30614617, PMID:38346941, PMID:37565374]. KDM7A directly binds promoters of context-specific target genes—including FGF4 in neural induction, C/EBPα and Sfrp1 in adipogenesis, DGAT2 in hepatocytes, FAP and RANKL in osteoprogenitor cells, and Fscn1 in reward-circuit neurons—and its catalytic activity is required for transcriptional activation, as demonstrated by catalytic-dead mutant controls [PMID:20084082, PMID:30614617, PMID:34681759, PMID:38346941, PMID:39836528]. Beyond canonical epigenetic functions, KDM7A stabilizes ICAM1 protein by suppressing TFEB-mediated lysosomal degradation independently of its demethylase activity on chromatin [PMID:27565733]. KDM7A is transcriptionally regulated by TGF-β signaling through SMAD2/SMAD4 binding at its own promoter and by nuclear miR-451a acting at an enhancer in an AGO2-dependent manner [PMID:34249916, PMID:38943031]."},"prefetch_data":{"uniprot":{"accession":"Q6ZMT4","full_name":"Lysine-specific demethylase 7A","aliases":["JmjC domain-containing histone demethylation protein 1D","Lysine-specific demethylase 7","[histone H3]-dimethyl-L-lysine9 demethylase 7A"],"length_aa":941,"mass_kda":106.6,"function":"Histone demethylase required for brain development. Specifically demethylates dimethylated 'Lys-9', 'Lys-27' and 'Lys-36' (H3K9me2, H3K27me2, H3K36me2, respectively) of histone H3 and monomethylated histone H4 'Lys-20' residue (H4K20Me1), thereby playing a central role in histone code (PubMed:20023638, PubMed:20622853). Specifically binds trimethylated 'Lys-4' of histone H3 (H3K4me3), affecting histone demethylase specificity: in presence of H3K4me3, it has no demethylase activity toward H3K9me2, while it has high activity toward H3K27me2. Demethylates H3K9me2 in absence of H3K4me3 (PubMed:20023638). Has activity toward H4K20Me1 only when nucleosome is used as a substrate and when not histone octamer is used as substrate (PubMed:20622853)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6ZMT4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KDM7A","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":[],"url":"https://opencell.sf.czbiohub.org/search/KDM7A","total_profiled":1310},"omim":[{"mim_id":"619640","title":"LYSINE DEMETHYLASE 7A; KDM7A","url":"https://www.omim.org/entry/619640"},{"mim_id":"609740","title":"PHD FINGER PROTEIN 19; PHF19","url":"https://www.omim.org/entry/609740"},{"mim_id":"604599","title":"EUCHROMATIC HISTONE-LYSINE N-METHYLTRANSFERASE 2; EHMT2","url":"https://www.omim.org/entry/604599"},{"mim_id":"300560","title":"PHD FINGER PROTEIN 8; PHF8","url":"https://www.omim.org/entry/300560"},{"mim_id":"192090","title":"CADHERIN 1; CDH1","url":"https://www.omim.org/entry/192090"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KDM7A"},"hgnc":{"alias_symbol":["KIAA1718"],"prev_symbol":["JHDM1D"]},"alphafold":{"accession":"Q6ZMT4","domains":[{"cath_id":"3.30.40.10","chopping":"39-95","consensus_level":"high","plddt":95.7398,"start":39,"end":95},{"cath_id":"2.60.120.650","chopping":"130-252_265-398","consensus_level":"high","plddt":97.7554,"start":130,"end":398},{"cath_id":"1.20.58.1360","chopping":"399-479","consensus_level":"medium","plddt":94.9517,"start":399,"end":479}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZMT4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZMT4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZMT4-F1-predicted_aligned_error_v6.png","plddt_mean":66.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KDM7A","jax_strain_url":"https://www.jax.org/strain/search?query=KDM7A"},"sequence":{"accession":"Q6ZMT4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZMT4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZMT4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZMT4"}},"corpus_meta":[{"pmid":"20084082","id":"PMC_20084082","title":"Dual-specificity histone demethylase KIAA1718 (KDM7A) regulates neural differentiation through FGF4.","date":"2010","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/20084082","citation_count":93,"is_preprint":false},{"pmid":"22143793","id":"PMC_22143793","title":"Increased expression of histone demethylase JHDM1D under nutrient starvation suppresses tumor growth via down-regulating angiogenesis.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22143793","citation_count":68,"is_preprint":false},{"pmid":"30614617","id":"PMC_30614617","title":"Histone demethylase KDM7A reciprocally regulates adipogenic and osteogenic differentiation via regulation of C/EBPα and canonical Wnt signalling.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30614617","citation_count":50,"is_preprint":false},{"pmid":"30183076","id":"PMC_30183076","title":"Histone demethylase KDM7A controls androgen receptor activity and tumor growth in prostate cancer.","date":"2018","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30183076","citation_count":46,"is_preprint":false},{"pmid":"26688070","id":"PMC_26688070","title":"G9a orchestrates PCL3 and KDM7A to promote histone H3K27 methylation.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26688070","citation_count":40,"is_preprint":false},{"pmid":"31739208","id":"PMC_31739208","title":"Long Non-coding RNA JHDM1D-AS1 Interacts with DHX15 Protein to Enhance Non-Small-Cell Lung Cancer Growth and Metastasis.","date":"2019","source":"Molecular therapy. 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and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32214833","citation_count":13,"is_preprint":false},{"pmid":"33245963","id":"PMC_33245963","title":"JHDM1D-AS1 aggravates the development of gastric cancer through miR-450a-2-3p-PRAF2 axis.","date":"2020","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33245963","citation_count":13,"is_preprint":false},{"pmid":"27565733","id":"PMC_27565733","title":"KDM7A histone demethylase mediates TNF-α-induced ICAM1 protein upregulation by modulating lysosomal activity.","date":"2016","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/27565733","citation_count":12,"is_preprint":false},{"pmid":"35903199","id":"PMC_35903199","title":"The Long Non-Coding Antisense RNA JHDM1D-AS1 Regulates Inflammatory Responses in Human Monocytes.","date":"2022","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35903199","citation_count":11,"is_preprint":false},{"pmid":"39509788","id":"PMC_39509788","title":"Structure-Based identification of a potent KDM7A inhibitor exerts anticancer activity through transcriptionally reducing MKRN1 in taxol- resistant and -sensitive triple-negative breast cancer cells.","date":"2024","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39509788","citation_count":10,"is_preprint":false},{"pmid":"34773593","id":"PMC_34773593","title":"LncRNA JHDM1D-AS1 Suppresses MPP + -Induced Neuronal Injury in Parkinson's Disease via miR-134-5p/PIK3R3 Axis.","date":"2021","source":"Neurotoxicity research","url":"https://pubmed.ncbi.nlm.nih.gov/34773593","citation_count":9,"is_preprint":false},{"pmid":"37565374","id":"PMC_37565374","title":"The Lysine Demethylase KDM7A Regulates Immediate Early Genes in Neurons.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37565374","citation_count":8,"is_preprint":false},{"pmid":"36903656","id":"PMC_36903656","title":"LncRNA JHDM1D-AS1 Is a Key Biomarker for Progression and Modulation of Gemcitabine Sensitivity in Bladder Cancer Cells.","date":"2023","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36903656","citation_count":8,"is_preprint":false},{"pmid":"39836528","id":"PMC_39836528","title":"The Histone Lysine Demethylase KDM7A Contributes to Reward Memory via Fscn1-Induced Synaptic Plasticity in the Medial Prefrontal Cortex.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39836528","citation_count":7,"is_preprint":false},{"pmid":"38756663","id":"PMC_38756663","title":"KDM7A-DT induces genotoxic stress, tumorigenesis, and progression of p53 missense mutation-associated invasive breast cancer.","date":"2024","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38756663","citation_count":6,"is_preprint":false},{"pmid":"38943031","id":"PMC_38943031","title":"Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38943031","citation_count":6,"is_preprint":false},{"pmid":"36862282","id":"PMC_36862282","title":"JHDM1D-AS1-driven inhibition of miR-940 releases ARTN expression to induce breast carcinogenesis.","date":"2023","source":"Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico","url":"https://pubmed.ncbi.nlm.nih.gov/36862282","citation_count":4,"is_preprint":false},{"pmid":"34395453","id":"PMC_34395453","title":"Corrigendum: The Jumonji Domain-Containing Histone Demethylase Homolog 1D/lysine Demethylase 7A (JHDM1D/KDM7A) Is an Epigenetic Activator of RHOJ Transcription in Breast Cancer Cells.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34395453","citation_count":4,"is_preprint":false},{"pmid":"37950511","id":"PMC_37950511","title":"LncRNA JHDM1D-AS1 promotes osteogenic differentiation of periodontal ligament cells by targeting miR-532-5p to activate IGF1R signaling.","date":"2023","source":"Journal of periodontal research","url":"https://pubmed.ncbi.nlm.nih.gov/37950511","citation_count":4,"is_preprint":false},{"pmid":"37909656","id":"PMC_37909656","title":"Kdm7a expression is spatiotemporally regulated in developing Xenopus laevis embryos, and its overexpression influences late retinal development.","date":"2023","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/37909656","citation_count":3,"is_preprint":false},{"pmid":"37623314","id":"PMC_37623314","title":"The dual functions of KDM7A in HBV replication and immune microenvironment.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/37623314","citation_count":2,"is_preprint":false},{"pmid":"41578150","id":"PMC_41578150","title":"Histone demethylase KDM7A negatively regulates fibrotic macrophage polarization and lung fibrosis progression.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41578150","citation_count":0,"is_preprint":false},{"pmid":"41296141","id":"PMC_41296141","title":"JHDM1D-AS1 Facilitates Progression of Colorectal Cancer via the miR-193b-3p/HPRT1 Axis.","date":"2025","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41296141","citation_count":0,"is_preprint":false},{"pmid":"41870972","id":"PMC_41870972","title":"KDM7A and KDM1A inhibition suppresses tumour promoting pathways in prostate cancer.","date":"2026","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41870972","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21751,"output_tokens":5124,"usd":0.071056},"stage2":{"model":"claude-opus-4-6","input_tokens":8662,"output_tokens":3727,"usd":0.204728},"total_usd":0.275784,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"KDM7A (KIAA1718) is a dual-specificity histone demethylase that removes di-methyl marks from both H3K9me2 and H3K27me2, and promotes neural differentiation through direct transcriptional activation of FGF4 by removing these repressive marks; catalytically inactive mutant fails to rescue neural differentiation knockdown phenotype.\",\n      \"method\": \"In vitro demethylase assay, catalytically inactive mutant rescue experiments, mouse embryonic stem cell knockdown/overexpression, RT-PCR\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic activity demonstrated, catalytic dead mutant used as control, multiple orthogonal methods, replicated in chick embryo model\",\n      \"pmids\": [\"20084082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KDM7A is predominantly expressed in epiblast cells of the primitive streak in early chick embryos, and its overexpression expands the neural plate while knockdown impairs neural plate formation; co-electroporation of Fgf4 rescues the KDM7A knockdown neural induction defect, placing KDM7A upstream of FGF4 in neural induction.\",\n      \"method\": \"In vivo chick embryo electroporation, knockdown/overexpression, genetic epistasis rescue with Fgf4\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with rescue experiment, consistent with mechanistic findings from PMID:20084082\",\n      \"pmids\": [\"20981832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"KDM7A (JHDM1D) suppresses tumor angiogenesis under nutrient starvation by downregulating expression of multiple angiogenic factors (VEGF-B, angiopoietins) in cancer cells, leading to reduced CD31+ blood vessel formation and CD11b+ macrophage infiltration in tumor xenografts.\",\n      \"method\": \"Stable cDNA expression and siRNA silencing in B16 and HeLa cells, in vivo xenograft tumor growth assays, immunohistochemistry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean gain/loss-of-function with defined in vivo phenotype, but mechanism linking demethylase activity to angiogenic factor regulation not dissected\",\n      \"pmids\": [\"22143793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"G9a promotes H3K27 methylation at the E-cadherin promoter partly by downregulating KDM7A; overexpression of KDM7A elevates E-cadherin expression in gemcitabine-resistant PANC-1-R cells, while knockdown of KDM7A downregulates E-cadherin in PANC-1 cells, placing KDM7A as an antagonist of G9a-mediated H3K27 methylation.\",\n      \"method\": \"Overexpression and knockdown in PANC-1 pancreatic cancer cells, ChIP, Western blot for histone marks and E-cadherin\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — epistasis defined through gain/loss-of-function and ChIP, single lab\",\n      \"pmids\": [\"26688070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM7A regulates TNF-α-induced ICAM1 protein upregulation via a lysosome-dependent pathway (not epigenetic/transcriptional): KDM7A knockdown reduces ICAM1 protein stability and promotes lysosomal degradation of ICAM1 by increasing TFEB-mediated lysosomal activity, without affecting ICAM1 mRNA levels.\",\n      \"method\": \"siRNA knockdown, cycloheximide chase, lysosome and proteasome inhibitor treatment, immunocytochemistry, Western blot in human brain microvascular endothelial cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (cycloheximide, inhibitors, immunocytochemistry) in single lab identifying a non-canonical post-translational mechanism\",\n      \"pmids\": [\"27565733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM7A binds to AR target-gene promoters upon androgen stimulation (ChIP), demethylates H3K27me2 at those promoters, and is required for androgen receptor-driven downstream gene expression and proliferation in prostate cancer cells.\",\n      \"method\": \"Stable shRNA knockdown in LNCaP cells, ChIP, Western blot for H3K27me2, AR target gene expression assays, xenograft tumor growth\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal ChIP and functional knockdown with defined phenotype in single lab\",\n      \"pmids\": [\"30183076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM7A directly binds to the promoters of C/EBPα and Sfrp1 (by ChIP), removes H3K9me2 and H3K27me2 marks, and promotes adipogenic over osteogenic differentiation in mesenchymal progenitor cells; enzymatic activity is required since a demethylase-dead point mutant fails to alter differentiation.\",\n      \"method\": \"ChIP assay, knockdown/overexpression with catalytic dead mutant in ST2 stromal cells and primary marrow stromal cells, adipogenic/osteogenic differentiation assays\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP demonstrating direct promoter binding plus catalytic dead mutant controls, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30614617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM7A is required for breast cancer stem cell (BCSC) maintenance by epigenetically upregulating stemness factors KLF4 and c-MYC, and inhibits apoptosis by upregulating BCL2; restoring BCL2 expression rescues apoptosis in KDM7A-knockdown cells, placing KDM7A upstream of BCL2-mediated apoptotic inhibition.\",\n      \"method\": \"siRNA knockdown, overexpression rescue, mammosphere formation assay, in vivo tumor growth, Western blot for BCL2/BAD phosphorylation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — defined cellular phenotype with rescue experiment, mechanistic link to BCL2 established by re-expression, single lab\",\n      \"pmids\": [\"31236965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KDM7A knockdown in porcine embryos increases H3K9me1/2 and H3K27me1/2 global levels, reduces blastocyst formation, reduces ICM/total cell ratio, and alters expression of pluripotency genes (NANOG, OCT4) and other KDMs, establishing KDM7A as required for early embryo development and first cell lineage specification.\",\n      \"method\": \"mRNA knockdown in porcine IVF/PA/SCNT embryos, immunofluorescence for histone marks, RT-PCR for pluripotency/KDM gene expression\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with multiple orthogonal readouts (IF for histone marks, gene expression, blastocyst rates), single lab\",\n      \"pmids\": [\"31216927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MKL1 physically interacts with and recruits KDM7A to the RHOJ promoter to cooperatively remove H3K9/H3K27 methylation, enabling TGF-β-induced RHOJ transcription and breast cancer cell migration/invasion; TGF-β induces KDM7A transcription via a SMAD2/SMAD4 complex binding to the KDM7A promoter.\",\n      \"method\": \"Co-immunoprecipitation (MKL1-KDM7A interaction), ChIP (KDM7A and histone marks at RHOJ promoter), siRNA knockdown, in vitro migration/invasion assays, in vivo xenograft, ChIP for SMAD2/SMAD4 at KDM7A promoter\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP for interaction, ChIP for promoter binding and histone marks, multiple functional readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34249916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM7A overexpression in hepatocytes upregulates DGAT2 by removing H3K9me2 and H3K27me2 from the DGAT2 promoter (ChIP), leading to increased triglyceride accumulation and hepatic steatosis; adenovirus-mediated KDM7A overexpression in mice reproduces hepatic steatosis in vivo.\",\n      \"method\": \"KDM7A overexpression/knockdown in AML12 cells, ChIP for H3K9me2/H3K27me2 at DGAT2 promoter, adenoviral overexpression in mice, triglyceride quantification\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP mechanistically links demethylase activity to DGAT2 promoter, in vivo validation, single lab\",\n      \"pmids\": [\"34681759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM7A/B demethylases regulate H3K79 methylation in chondrocytes; individual siRNA silencing of KDM7A or KDM7B in human chondrocytes increases H3K79me and glycosaminoglycan content, and intra-articular daminozide (KDM2/7 inhibitor) protects against osteoarthritis in a mouse DMM model.\",\n      \"method\": \"Individual siRNA silencing of KDM7A/B, Western blot and immunofluorescence for H3K79me, Alcian blue staining, in vivo DMM mouse model with intra-articular injection\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — individual gene silencing with defined epigenetic and functional readouts, in vivo validation, but combined with pharmacological inhibitor targeting both KDM7A and KDM7B\",\n      \"pmids\": [\"36927643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM7A knockdown in N2A neuronal cells and mouse hippocampal dentate gyrus neurons reduces H3K9me1/2 and H3K27me1/2 enrichment near transcription start sites and markedly decreases expression of immediate early genes (IEGs); in vivo Kdm7a knockdown via AAV impairs hippocampal c-Fos expression, neuronal activity, emotion, and memory in mice.\",\n      \"method\": \"CUT&Tag-seq (histone marks), RNA-seq, AAV-mediated in vivo knockdown, behavioral assays in mice, immunofluorescence\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide CUT&Tag and RNA-seq combined with in vivo AAV knockdown and behavior, multiple orthogonal methods\",\n      \"pmids\": [\"37565374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM7A removes H3K9me2 and H3K27me2 from the Fap (fibroblast activation protein α) and Rankl promoters in osteoprogenitor cells, upregulating FAP and RANKL expression; conditional Kdm7a deletion in osterix+ cells in mice increases cancellous bone mass, enhances osteoblast differentiation, reduces osteoclast differentiation, and protects against ovariectomy-induced bone loss.\",\n      \"method\": \"Conditional knockout mouse (osterix-Cre), ChIP for H3K9me2/H3K27me2 at Fap and Rankl promoters, bone histomorphometry, co-culture of BMSCs with osteoclast precursors, recombinant FAP rescue\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — conditional KO with in vivo phenotype, ChIP identifying direct promoter targets, rescue with recombinant FAP, multiple orthogonal methods\",\n      \"pmids\": [\"38346941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM7A knockdown in mPFC neurons reduces H3K9me2 and H3K27me2 enrichment at the Fscn1 promoter, decreasing Fscn1 expression, dendritic spine density, and neuronal activity, leading to impaired morphine-conditioned place preference memory consolidation.\",\n      \"method\": \"AAV-mediated Kdm7a knockdown in mouse mPFC, Nanopore direct RNA sequencing, ChIP for H3K9me2/H3K27me2 at Fscn1 promoter, behavioral CPP assay, dendritic spine imaging\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo AAV knockdown, ChIP, transcriptomics, and behavioral assays providing multiple orthogonal lines of evidence\",\n      \"pmids\": [\"39836528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nuclear miR-451a activates KDM7A transcription by interacting with an enhancer region in the KDM7A locus in an AGO2-dependent manner, leading to increased KDM7A expression and cetuximab resistance in head and neck squamous cell carcinoma.\",\n      \"method\": \"Small RNA sequencing, FISH for nuclear miR-451a localization, ChIRP (chromatin isolation by RNA purification), siRNA knockdown, microarray analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIRP for RNA-chromatin interaction plus functional knockdown, but mechanism linking KDM7A upregulation to cetuximab resistance is not fully dissected at the enzymatic level\",\n      \"pmids\": [\"38943031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A KDM7A inhibitor (compound 4) blocks KDM7A binding to H3K27me3, reduces MKRN1 transcription (identifying MKRN1 as a downstream target of KDM7A), and increases cell cycle inhibitors p16, p21, p27 while reducing breast cancer stem cell markers in triple-negative breast cancer cells.\",\n      \"method\": \"Structure-based virtual screening, in vitro demethylase inhibition assay, ChIP (KDM7A binding to H3K27me3), gene expression analysis, cell cycle assay\",\n      \"journal\": \"Bioorganic chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — in vitro demethylase activity inhibition and ChIP evidence for target gene regulation, single lab\",\n      \"pmids\": [\"39509788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KDM7A interacts with covalently closed circular DNA (cccDNA) of HBV to promote HBV replication, and also downregulates the IFN-γ/JAK2/STAT1 signaling pathway in macrophages and hepatocytes.\",\n      \"method\": \"Described as mechanistic study (specific methods not detailed in abstract; interaction with cccDNA and signaling pathway downregulation reported)\",\n      \"journal\": \"Microbiology spectrum\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — limited methodological detail in abstract, single report\",\n      \"pmids\": [\"37623314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KDM7A suppresses profibrotic macrophage (Fib-Mac) polarization by maintaining H3K27me2 at the TLR8 enhancer to promote TLR8 expression; Kdm7a knockout in mice expands Fib-Mac populations and exacerbates bleomycin-induced lung fibrosis.\",\n      \"method\": \"Kdm7a conditional knockout mice, single-cell RNA sequencing, bleomycin lung fibrosis model, ChIP/epigenetic analysis at TLR8 enhancer\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO phenotype with scRNA-seq and epigenetic mechanistic data at TLR8 enhancer, single lab\",\n      \"pmids\": [\"41578150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kdm7a overexpression in Xenopus does not affect early neural/eye-field specification genes but alters retinal neuronal subtype distribution in the mature retina, disfavoring ganglion cells and promoting horizontal cells, suggesting a role in the timing of retinal neurogenesis.\",\n      \"method\": \"Xenopus overexpression (ortholog study), retinal cell subtype quantification, in situ hybridization for kdm7a expression pattern\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — overexpression in Xenopus ortholog without mechanistic dissection of demethylase targets; phenotype described without pathway placement\",\n      \"pmids\": [\"37909656\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM7A is a dual-specificity histone demethylase that removes mono- and di-methyl marks from H3K9 (me1/2) and H3K27 (me1/2) to activate transcription of target genes; it regulates neural differentiation via FGF4, adipogenic/osteogenic lineage balance via C/EBPα and Sfrp1/Wnt signaling, androgen receptor-driven gene expression in prostate cancer, hepatic lipid metabolism via DGAT2, neuronal immediate early genes and reward memory via Fscn1, and bone homeostasis via FAP and RANKL, while also acting through non-canonical mechanisms such as lysosome-mediated ICAM1 protein stabilization, and its transcription is regulated upstream by TGF-β/SMAD2/SMAD4 and nuclear miR-451a/AGO2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KDM7A is a dual-specificity JmjC-domain histone demethylase that removes mono- and di-methyl marks from H3K9 and H3K27, thereby relieving transcriptional repression at target gene promoters to regulate neural differentiation, mesenchymal lineage commitment, bone homeostasis, hepatic lipid metabolism, and neuronal immediate-early gene expression [PMID:20084082, PMID:30614617, PMID:38346941, PMID:37565374]. KDM7A directly binds promoters of context-specific target genes—including FGF4 in neural induction, C/EBPα and Sfrp1 in adipogenesis, DGAT2 in hepatocytes, FAP and RANKL in osteoprogenitor cells, and Fscn1 in reward-circuit neurons—and its catalytic activity is required for transcriptional activation, as demonstrated by catalytic-dead mutant controls [PMID:20084082, PMID:30614617, PMID:34681759, PMID:38346941, PMID:39836528]. Beyond canonical epigenetic functions, KDM7A stabilizes ICAM1 protein by suppressing TFEB-mediated lysosomal degradation independently of its demethylase activity on chromatin [PMID:27565733]. KDM7A is transcriptionally regulated by TGF-β signaling through SMAD2/SMAD4 binding at its own promoter and by nuclear miR-451a acting at an enhancer in an AGO2-dependent manner [PMID:34249916, PMID:38943031].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing that KDM7A possesses intrinsic dual-specificity demethylase activity toward H3K9me2 and H3K27me2 resolved the enzymatic identity of this JmjC-domain protein and linked it to neural differentiation via FGF4 transcriptional activation.\",\n      \"evidence\": \"In vitro demethylase assay with catalytic-dead mutant control, mouse ESC knockdown/overexpression, and chick embryo electroporation with FGF4 epistasis rescue\",\n      \"pmids\": [\"20084082\", \"20981832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for dual H3K9/H3K27 substrate recognition not determined\",\n        \"Whether H3K9me1 and H3K27me1 are also substrates was not systematically tested in vitro at this stage\",\n        \"Upstream signals controlling KDM7A during neural induction were unknown\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that KDM7A suppresses tumor angiogenesis under nutrient stress expanded its biology beyond development, though the direct chromatin targets mediating angiogenic factor downregulation remained undefined.\",\n      \"evidence\": \"Stable overexpression/siRNA in cancer cells, xenograft assays with immunohistochemistry for CD31 and CD11b\",\n      \"pmids\": [\"22143793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No ChIP evidence identifying direct promoter targets of KDM7A at angiogenic factor loci\",\n        \"Catalytic-dead mutant not tested, so demethylase-dependence not confirmed\",\n        \"Single lab without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that KDM7A regulates ICAM1 protein stability through lysosomal degradation (TFEB pathway) without affecting ICAM1 mRNA revealed a non-canonical, non-epigenetic function for this demethylase.\",\n      \"evidence\": \"siRNA knockdown in brain microvascular endothelial cells, cycloheximide chase, lysosome/proteasome inhibitors\",\n      \"pmids\": [\"27565733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether this non-epigenetic function requires demethylase catalytic activity is unknown\",\n        \"Direct physical interaction between KDM7A and TFEB or lysosomal machinery not shown\",\n        \"Not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that KDM7A is recruited to androgen receptor target-gene promoters upon androgen stimulation to remove H3K27me2 established KDM7A as a hormone-responsive transcriptional coactivator in prostate cancer.\",\n      \"evidence\": \"shRNA knockdown in LNCaP cells, ChIP for KDM7A and H3K27me2 at AR target promoters, xenograft growth\",\n      \"pmids\": [\"30183076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between KDM7A and AR not demonstrated\",\n        \"Whether H3K9me2 demethylation also occurs at AR target loci was not addressed\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ChIP-based identification of C/EBPα and Sfrp1 promoters as direct KDM7A targets—together with catalytic-dead mutant failure to drive adipogenesis—established that enzymatic H3K9me2/H3K27me2 demethylation controls mesenchymal lineage commitment between adipogenic and osteogenic fates.\",\n      \"evidence\": \"ChIP, overexpression/knockdown with catalytic-dead mutant in ST2 and primary marrow stromal cells, differentiation assays\",\n      \"pmids\": [\"30614617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vivo bone/fat phenotype from conditional knockout not yet reported at this time\",\n        \"Whether KDM7A acts downstream of specific signaling cues in marrow was not identified\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"KDM7A knockdown in porcine embryos increased global H3K9me1/2 and H3K27me1/2 and impaired blastocyst formation, establishing that KDM7A-dependent demethylation is necessary for early embryonic development and first lineage specification.\",\n      \"evidence\": \"mRNA knockdown in IVF/PA/SCNT porcine embryos, immunofluorescence, RT-PCR for pluripotency genes\",\n      \"pmids\": [\"31216927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific promoter targets in early embryos not identified by ChIP\",\n        \"Rescue with wild-type or catalytic-dead KDM7A not performed\",\n        \"Porcine system; relevance to human embryogenesis not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of MKL1 as a physical partner that recruits KDM7A to the RHOJ promoter, and of SMAD2/SMAD4 as direct transcriptional activators of KDM7A itself, placed KDM7A within TGF-β signaling and explained how its expression and chromatin targeting are regulated during cancer cell invasion.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP at RHOJ and KDM7A promoters, knockdown, xenograft assays\",\n      \"pmids\": [\"34249916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether MKL1-KDM7A interaction is direct or bridged was not resolved\",\n        \"Genome-wide scope of MKL1-KDM7A co-occupancy not mapped\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ChIP evidence that KDM7A removes H3K9me2/H3K27me2 at the DGAT2 promoter to drive triglyceride accumulation linked the demethylase to hepatic lipid metabolism and steatosis in vivo.\",\n      \"evidence\": \"Overexpression/knockdown in AML12 cells, ChIP at DGAT2 promoter, adenoviral overexpression in mouse liver\",\n      \"pmids\": [\"34681759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Catalytic-dead mutant not tested in the hepatocyte system\",\n        \"Conditional hepatocyte knockout not generated\",\n        \"Upstream signals inducing KDM7A in steatotic conditions not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Genome-wide CUT&Tag and RNA-seq in neurons combined with in vivo AAV knockdown showed that KDM7A maintains H3K9me1/2 and H3K27me1/2 at TSS regions and is essential for immediate-early gene expression, neuronal activity, and memory, establishing a CNS-specific functional role.\",\n      \"evidence\": \"CUT&Tag-seq, RNA-seq in N2A cells, AAV-mediated hippocampal knockdown in mice, behavioral assays\",\n      \"pmids\": [\"37565374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct promoter targets among IEGs not validated by individual ChIP\",\n        \"Cell-type specificity within hippocampal subpopulations not resolved\",\n        \"Whether catalytic activity is required for IEG regulation was not tested with mutant\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Conditional deletion of Kdm7a in osterix+ osteoprogenitors increased bone mass and protected against ovariectomy-induced bone loss by reducing FAP and RANKL at the promoter level, providing definitive in vivo genetic evidence for KDM7A in bone homeostasis.\",\n      \"evidence\": \"Osterix-Cre conditional knockout, ChIP at Fap/Rankl promoters, bone histomorphometry, recombinant FAP rescue, co-culture assays\",\n      \"pmids\": [\"38346941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Therapeutic targeting of KDM7A in osteoporosis not tested with specific inhibitors\",\n        \"Whether KDM7A also regulates osteoclast-intrinsic programs is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of Fscn1 as a direct KDM7A target in mPFC neurons linked the demethylase to dendritic spine remodeling and reward memory consolidation, extending its neuronal role beyond hippocampal IEGs.\",\n      \"evidence\": \"AAV knockdown in mouse mPFC, Nanopore RNA-seq, ChIP at Fscn1 promoter, dendritic spine imaging, conditioned place preference\",\n      \"pmids\": [\"39836528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether KDM7A-Fscn1 axis generalizes to other forms of memory not tested\",\n        \"Catalytic-dead rescue not performed in this brain region\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Nuclear miR-451a was found to activate KDM7A transcription via enhancer interaction in an AGO2-dependent manner, revealing a non-canonical RNA-mediated mechanism of KDM7A gene regulation beyond the previously known SMAD-dependent pathway.\",\n      \"evidence\": \"ChIRP, small RNA sequencing, FISH, siRNA knockdown in HNSCC cells\",\n      \"pmids\": [\"38943031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether miR-451a/AGO2 mechanism operates in non-cancer contexts is unknown\",\n        \"Direct causal link between KDM7A upregulation and cetuximab resistance not fully dissected at the epigenetic level\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for KDM7A's dual H3K9/H3K27 substrate specificity, the full repertoire of its non-epigenetic functions, and whether selective KDM7A inhibitors can be developed for therapeutic applications in bone loss, neurological disorders, or cancer.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal structure of KDM7A in complex with nucleosomal substrates\",\n        \"Mechanism of the non-canonical lysosomal/TFEB-related function remains unresolved\",\n        \"Genome-wide mapping of KDM7A chromatin occupancy across tissues is lacking\",\n        \"No selective KDM7A inhibitor with validated in vivo pharmacokinetics\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 6, 8, 12, 13, 14]},\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 6, 10, 13]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 5, 6, 10, 13, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 6, 9, 10, 13, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 6, 9, 10, 13, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 5, 6, 8, 9, 10, 12, 13, 14]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 5, 6, 10, 12, 13, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 5, 6, 8, 10, 12, 13, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 6, 9, 10, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 6, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"MKL1\",\n      \"SMAD2\",\n      \"SMAD4\",\n      \"AGO2\",\n      \"AR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}