{"gene":"KDM5C","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2007,"finding":"KDM5C (SMCX/JARID1C) is a histone H3K4me3 demethylase that converts H3K4me3 to di- and mono-methylated products but not to unmethylated H3K4; its N-terminal PHD finger binds H3K9me3, potentially coordinating H3K4 demethylation with H3K9 methylation in transcriptional repression.","method":"In vitro histone demethylase assay, peptide binding assays, site-directed mutagenesis; zebrafish and primary neuron knockdown experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic reconstitution with mechanistic follow-up, replicated across multiple family members, validated in vivo","pmids":["17320160"],"is_preprint":false},{"year":2007,"finding":"A KDM5C-containing complex isolated from HeLa cells includes the histone deacetylases HDAC1 and HDAC2, the H3K9 methyltransferase G9a, and the transcriptional repressor REST; KDM5C and REST co-occupy neuron-restrictive silencing elements in promoters of REST target genes (SCN2A, SYN1), and KDM5C depletion derepresses these targets while increasing H3K4me3 at their promoters.","method":"Complex purification from HeLa cells, reciprocal co-immunoprecipitation, ChIP, RNAi-mediated knockdown with transcriptional and histone modification readouts","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP, and functional derepression assay in a single study","pmids":["17468742"],"is_preprint":false},{"year":2007,"finding":"KDM5C requires multiple functional domains for H3K4me3 demethylase activity, can form homomers through amino acids 204–493, and physically interacts with Smad3; overexpression of KDM5C inhibits Smad3-mediated transcriptional activation, acting as a Smad3 corepressor.","method":"Co-immunoprecipitation, domain-deletion mutagenesis, reporter gene transcription assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP and reporter assay, single lab","pmids":["18078810"],"is_preprint":false},{"year":2011,"finding":"PCNA is required for loading KDM5C onto chromatin; KDM5C contains a PIP box motif, and mutation of PIP box residues disrupts KDM5C–PCNA interaction and reduces the chromatin-bound fraction of KDM5C.","method":"siRNA knockdown of PCNA, site-directed mutagenesis of PIP box, chromatin fractionation","journal":"Epigenetics & chromatin","confidence":"Medium","confidence_rationale":"Tier 2 — mutagenesis combined with fractionation, but single lab","pmids":["21996408"],"is_preprint":false},{"year":2012,"finding":"ARX directly regulates KDM5C expression by binding a conserved noncoding element in its regulatory region; polyalanine-expansion mutations in ARX reduce binding to this element and decrease KDM5C mRNA levels, which in turn reduces KDM5C protein and leads to increased H3K4me3 and failure to repress downstream neuronal targets (Scn2a, Syn1, Bdnf).","method":"Reporter assays, quantitative RT-PCR in Arx-KO cells, ChIP, chromatin immunoprecipitation, in vitro neuronal differentiation","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (reporter, ChIP, qRT-PCR) in single lab","pmids":["23246292"],"is_preprint":false},{"year":2015,"finding":"KDM5C is required for proper DNA replication at early origins; KDM5C demethylates H3K4me3 to drive the assembly of the pre-initiation complex, facilitating chromatin binding of CDC45 and PCNA, and its knockdown impairs replication origin firing without affecting fork activation or H4 acetylation.","method":"siRNA knockdown, ChIP, DNA replication assays, measurement of pre-initiation complex protein chromatin binding","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic epistasis shown by knockdown with multiple chromatin and replication readouts, single lab","pmids":["25712104"],"is_preprint":false},{"year":2015,"finding":"KDM5C localizes on heterochromatin (characterized by H3K9me3), is required for heterochromatin replication, and forms a complex with SUV39H1, HP1α, and the CUL4 complex adaptor DDB1; KDM5C inactivation leads to derepression of heterochromatic noncoding RNAs, triggering genomic instability.","method":"ChIP-seq, Co-immunoprecipitation, knockdown with ncRNA expression and genomic instability readouts, ccRCC patient sample analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP-seq, Co-IP, functional knockdown, patient validation) supporting mechanism","pmids":["26551685"],"is_preprint":false},{"year":2015,"finding":"Patient-associated KDM5C missense mutations (P480L, D402Y) reduce protein stability and enzymatic demethylase activity; a start-codon mutation (c.2T>C) causes production of an N-terminally truncated protein lacking detectable demethylase activity; a frameshift (c.3223delG) leads to complete protein loss; patient fibroblasts show upregulation of specific target genes consistent with local chromatin changes.","method":"Primary patient cell biochemistry, in vitro demethylase activity assays, protein stability measurements, gene expression analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay combined with patient cell validation across multiple mutations","pmids":["25666439"],"is_preprint":false},{"year":2015,"finding":"KDM5C patient mutation P554T compromises both tri- and di-demethylase activity in functional assays.","method":"In vitro demethylase activity assay on recombinant protein carrying patient mutations","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 1 method — in vitro assay, but single mutation in single study","pmids":["19826449"],"is_preprint":false},{"year":2017,"finding":"Kdm5c acts in neurons as a transcriptional repressor responsible for developmental silencing of germline genes during cellular differentiation and for fine-tuning activity-regulated enhancers during neuronal maturation; in adult neurons it prevents incorrect activation of non-neuronal and cryptic promoters.","method":"Kdm5c-null and forebrain-restricted inducible knockout mice; parallel behavioral, transcriptomic, and epigenomic analyses; chromatin accessibility and gene expression assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple orthogonal omics readouts and functional assays in vivo","pmids":["28978483"],"is_preprint":false},{"year":2018,"finding":"HPV16 E6 oncoprotein physically interacts with KDM5C and promotes its degradation in an E6AP E3 ligase- and proteasome-dependent manner; KDM5C degradation activates super-enhancers of EGFR and c-MET by modulating H3K4me3/H3K4me1 dynamics and increasing bidirectional enhancer RNA transcription.","method":"Co-immunoprecipitation, protein stability assays, ChIP-seq, RNA-seq, gain/loss-of-function in cervical cancer cells","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, proteomics, genome-wide ChIP-seq, and RNA-seq with mechanistic follow-up","pmids":["29339538"],"is_preprint":false},{"year":2018,"finding":"KDM5C-R1115H mutation does not affect enzymatic activity or protein stability but fails to fully suppress target gene expression in post-mitotic neurons and alters expression of a distinct gene set compared to wild-type, suggesting KDM5C has non-enzymatic roles in gene regulation.","method":"Enzymatic activity assays, protein stability measurements, overexpression in primary neurons with transcriptomic readout","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — functional assays in neurons with transcriptomic readout, single lab","pmids":["29670509"],"is_preprint":false},{"year":2019,"finding":"ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression at its promoter and compete for recruitment of PHF8; functional mutations in ARX, ZNF711, and PHF8 reduce KDM5C transcriptional activity, and this reduction correlates with severity of neurodevelopmental phenotype and elevated H3K4me3 at downstream targets (Scn2a, Syn1, Bdnf).","method":"KDM5C promoter reporter assays, ChIP, qRT-PCR in Arx-KO murine ES-derived neurons, C. elegans alr-1 rescue experiments with SAHA","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple reporter and ChIP experiments, cross-species validation, single lab","pmids":["31691806"],"is_preprint":false},{"year":2020,"finding":"Functional interactions between the H3K4me writer KMT2A and the H3K4me eraser KDM5C are mutually suppressive: double mutation of Kmt2a and Kdm5c in mice reverses dendritic morphology deficits, key behavioral traits (including aggression), and partially corrects altered H3K4me landscapes seen in single mutants.","method":"Double-mutant mouse epistasis, dendritic spine morphology, behavioral assays, H3K4me ChIP, transcriptomics","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo with multiple orthogonal readouts","pmids":["32483278"],"is_preprint":false},{"year":2020,"finding":"Kdm5c gene dosage (as an X-chromosome escapee) influences chromatin accessibility, gene expression in preadipocytes (including extracellular matrix remodeling genes), and adipocyte differentiation; modulating Kdm5c dosage in female mice to male levels reduces body weight, fat content, and food intake.","method":"ATAC-seq, RNA-seq in cultured preadipocytes; in vivo Kdm5c heterozygous and hemizygous mouse models with body composition measurements","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo experiments with genome-wide readouts and physiological phenotyping","pmids":["32701509"],"is_preprint":false},{"year":2021,"finding":"KDM5C deficiency in ccRCC cells reprograms glycogen metabolism by upregulating HIF-related genes and G6PD (via loss of H3K4 demethylase activity at their promoters), directing glucose flux to the pentose phosphate pathway and increasing NADPH/GSH to confer resistance to ferroptosis.","method":"RNA-seq, metabolomics, heavy isotope tracer analysis, ChIP, CRISPR-Cas9 Kdm5c-knockout mice, xenograft models","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — multi-omics with ChIP, metabolic tracing, in vivo KO validation","pmids":["34522206"],"is_preprint":false},{"year":2021,"finding":"KDM5C acts as a transcriptional repressor at promoters through its H3K4me3 demethylase activity; KDM5C knockdown results in globally increased H3K4me3 and upregulation of bivalently marked immature genes, producing a de-differentiation phenotype in AML cells both in vitro and in vivo.","method":"In vivo shRNA screen, ChIP-seq, RNA-seq, murine and human AML cell lines and mouse models","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — in vivo screen combined with genome-wide ChIP-seq and transcriptomics with functional phenotype","pmids":["36631623"],"is_preprint":false},{"year":2021,"finding":"KDM5C binds to active enhancers and recruits the P-TEFb complex to activate ERα-target genes, while also inhibiting TBK1 phosphorylation in the cytosol to repress type I interferons and ISGs; ZMYND8 is involved in both processes.","method":"Co-immunoprecipitation, ChIP-seq, RNA-seq, kinase phosphorylation assays in breast cancer cells","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq and Co-IP with functional assays, but dual activator/repressor mechanism from single lab","pmids":["33977073"],"is_preprint":false},{"year":2022,"finding":"KDM5C activates Xist lncRNA expression by converting H3K4me2/3 to H3K4me1 at the Xist locus; Kdm5c ablation significantly reduces Xist RNA in female cells; ectopic expression of mouse/human KDM5C (but not Y-linked KDM5D) induces Xist in male mESCs, and this function is conserved in marsupial and even monotreme KDM5C orthologs.","method":"Kdm5c knockout in female mESCs, ectopic expression in male mESCs, ChIP for H3K4 methylation states, RNA FISH for Xist, cross-species functional comparison","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — genetic KO with molecular readout, gain-of-function validation, cross-species conservation tested","pmids":["35545632"],"is_preprint":false},{"year":2022,"finding":"The ARID domain of KDM5C is required for efficient nucleosome demethylation, while the PHD1 domain has an inhibitory role in KDM5C catalysis by inhibiting DNA recognition; the unstructured linker between ARID and PHD1 interacts with PHD1 and is necessary for nucleosome binding; XLID mutations adjacent to these domains enhance DNA binding and reduce substrate specificity.","method":"In vitro binding and kinetic studies with purified nucleosomes, domain-deletion mutagenesis, XLID mutation analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with nucleosomes, kinetic assays, mutagenesis","pmids":["36495919"],"is_preprint":false},{"year":2022,"finding":"TRIM11 is an E3 ubiquitin ligase for KDM5C that interacts with KDM5C, catalyzes K48-linked ubiquitin chains on KDM5C, and promotes its proteasomal degradation; TRIM11 deficiency stabilizes KDM5C and represses breast tumor growth; KDM5C and TRIM11 regulate MCAM enhancer activity through H3K4me3 modulation.","method":"Co-immunoprecipitation, ubiquitination assays, in vivo animal model, ChIP-seq, RNA-seq","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assay, in vivo validation, ChIP-seq","pmids":["36192394"],"is_preprint":false},{"year":2024,"finding":"KDM5C directly controls WNT signaling output during a specific developmental window to regulate the timely transition of primary to intermediate progenitor cells and neurogenesis; KDM5C depletion dysregulates canonical WNT pathway, and transient WNT inhibition rescues transcriptomic and chromatin landscapes in patient-derived iPSCs and behavioral changes in Kdm5c knockout mice.","method":"Patient iPSC-derived neurons, Kdm5c KO mice, transcriptomics, chromatin profiling, WNT modulator rescue experiments, behavioral assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — in vitro patient iPSC and in vivo mouse KO with transcriptomic, chromatin, and behavioral rescue, replicated","pmids":["38383780"],"is_preprint":false},{"year":2024,"finding":"KDM5C interacts with BRD4 and stimulates BRD4 enhancer recruitment; conversely, the BRD4 C-terminus binding to KDM5C stimulates KDM5C H3K4 demethylase activity; the abundance of KDM5C-associated BRD4 and H3K4me1/3 determines transcriptional activation of oncogenes; KDM5C depletion reduces BRD4 chromatin enrichment and enhances BET inhibitor efficacy.","method":"Co-immunoprecipitation, ChIP-seq, in vitro demethylase activity assays, xenograft mouse model, patient-derived organoids","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ChIP-seq, in vitro activity assay, in vivo validation, patient organoids","pmids":["38285760"],"is_preprint":false},{"year":2024,"finding":"KDM5C regulates dendritic cell (DC) population heterogeneity and function; KDM5C-deficient DCs show increased inflammatory gene expression, altered lineage-specific gene expression, and decreased antigen presentation by cDC1s; the effect on cDC2B and cDC1 proportions is partly dependent on type I IFN and pDCs.","method":"DC-specific Kdm5c conditional KO mice, flow cytometry, RNA-seq, Listeria infection model with CD8 T cell response readout","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with multiple cellular and transcriptomic readouts, single lab","pmids":["39052479"],"is_preprint":false},{"year":2024,"finding":"Decreased KDM5C expression in diabetic plasmacytoid dendritic cells increases IL-6 transcription, which skews naive CD4+ T cells toward a Th17 phenotype; this process is regulated upstream by an IFN-I/TYK2/JAK1,3 signaling pathway; inhibiting KDM5C in non-diabetic wound pDCs mimics the diabetic Th17-skewing phenotype.","method":"Human tissue and murine wound healing models, genetic inhibition/overexpression, cytokine measurements, T cell co-culture assays, pathway inhibitor experiments","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse model and human tissue with mechanistic pathway dissection, single lab","pmids":["38912581"],"is_preprint":false},{"year":2025,"finding":"KDM5C interacts with CRBN (cereblon) and stabilizes CRBN protein in an enzyme activity-independent manner, thereby enhancing the antileukemia effect of lenalidomide in AML cells.","method":"TurboID proximity labeling, quantitative proteomics, Co-immunoprecipitation, cell viability assays in AML lines and primary cells, KDM5C inhibitors","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 — proximity labeling proteomics and Co-IP with functional validation, single lab","pmids":["39881283"],"is_preprint":false},{"year":2024,"finding":"YY1 interacts with KDM5C, and KDM5C promotes global YY1 chromatin recruitment especially at promoters in a manner requiring an intact KDM5C JmjC domain but not its demethylase catalytic activity; dual inhibition of KDM5C and YY1 is synergistically lethal and increases transcriptional repression of cell cycle- and apoptosis-related genes.","method":"Protein interaction screen, Co-immunoprecipitation, ChIP-seq, RNA-seq, genetic knockdown, domain mutants","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, ChIP-seq, and transcriptomics with domain mutant mechanistic follow-up, single lab","pmids":["39433896"],"is_preprint":false},{"year":2016,"finding":"KDM5C suppresses miR-320a transcription by directly binding to the miR-320a promoter to prevent histone H3K4 methylation; KITLG, an essential gene for ovarian development, is a direct target of miR-320a and is downregulated in 45,X gonadal tissues where KDM5C dosage is reduced.","method":"ChIP, in vitro promoter binding, miRNA/target validation assays, expression analysis in Turner syndrome (45,X) samples","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP with functional promoter binding, multi-sample validation, single lab","pmids":["27896428"],"is_preprint":false},{"year":2025,"finding":"In male bone marrow mesenchymal stromal cells (MSCs), lower Kdm5c expression leads to increased Cxcl12 expression; MSC-specific Kdm5c knockout in female mice increases MSC quantity and function, enhancing hematopoietic engraftment to male levels.","method":"Single-cell RNA-seq, MSC-specific Kdm5c KO mice, bone marrow transplantation assays, co-culture experiments","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KO with in vivo functional readout, scRNA-seq, single lab","pmids":["39836478"],"is_preprint":false}],"current_model":"KDM5C is an X-linked histone H3K4me2/3 demethylase whose JmjC catalytic domain reverses H3K4me3 to H3K4me2/me1; its activity is modulated by accessory domains (ARID required for nucleosome demethylation; PHD1 inhibitory, relieved by H3 tail engagement), by cofactor interactions (REST/HDAC1/HDAC2/G9a complex for neuronal gene silencing; BRD4 for enhancer regulation; PCNA for chromatin loading), and by post-translational control (TRIM11-mediated K48-ubiquitylation and proteasomal degradation; HPV E6-triggered E6AP-dependent degradation); KDM5C plays essential roles in transcriptional repression of neuronal and germline genes, activation of Xist for X-inactivation, regulation of heterochromatin integrity, DNA replication origin firing, WNT-controlled neurogenesis timing, and immune cell function, with loss-of-function causing X-linked intellectual disability and multiple cancer-associated phenotypes."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing KDM5C as an H3K4me3 demethylase and identifying its REST/HDAC1/HDAC2/G9a repressive complex resolved the molecular function and immediate chromatin context for KDM5C-mediated transcriptional silencing of neuronal genes.","evidence":"In vitro demethylase assays, peptide binding, complex purification from HeLa, reciprocal Co-IP, ChIP, and RNAi derepression of REST targets","pmids":["17320160","17468742"],"confidence":"High","gaps":["Structural basis of KDM5C–REST complex assembly unknown","Relative contribution of demethylase versus scaffold function not separated","In vivo neuronal consequence of complex disruption not tested"]},{"year":2011,"claim":"Identifying PCNA-dependent chromatin loading of KDM5C via a PIP box motif linked histone demethylation to the DNA replication machinery, later extended by the finding that KDM5C demethylates H3K4me3 at early origins to promote pre-initiation complex assembly and origin firing.","evidence":"PIP box mutagenesis with chromatin fractionation; siRNA knockdown with ChIP and DNA replication assays","pmids":["21996408","25712104"],"confidence":"Medium","gaps":["Whether KDM5C acts at all origins or a subset is unknown","Direct physical contacts between KDM5C and pre-IC components beyond PCNA not established"]},{"year":2015,"claim":"Demonstrating that KDM5C localizes to H3K9me3-marked heterochromatin in a complex with SUV39H1/HP1α/DDB1, and that its loss causes heterochromatic ncRNA derepression and genomic instability, established a tumor-suppressive role beyond euchromatic gene regulation.","evidence":"ChIP-seq, Co-IP, knockdown with ncRNA and instability readouts, ccRCC patient sample analysis","pmids":["26551685"],"confidence":"High","gaps":["Whether DDB1/CUL4 ubiquitylates a KDM5C substrate at heterochromatin is unknown","Mechanism connecting ncRNA derepression to genomic instability not resolved"]},{"year":2015,"claim":"Biochemical characterization of XLID-associated KDM5C mutations (P480L, D402Y, P554T, start-codon loss, frameshift) directly linked reduced demethylase activity or protein loss to disease, establishing the enzymatic basis of X-linked intellectual disability.","evidence":"In vitro demethylase assays on recombinant mutant proteins, patient fibroblast gene expression and protein stability measurements","pmids":["25666439","19826449"],"confidence":"High","gaps":["Not all XLID mutations reduce catalytic activity — non-enzymatic pathogenic mechanisms remain unclear","Structure–function relationship for most mutations not resolved at atomic level"]},{"year":2017,"claim":"Conditional knockout in mouse forebrain neurons revealed that KDM5C silences germline genes during differentiation and fine-tunes activity-regulated enhancers during maturation, establishing its dual role as a developmental and experience-dependent chromatin regulator in neurons.","evidence":"Kdm5c-null and forebrain-specific inducible KO mice with parallel behavioral, transcriptomic, and epigenomic profiling","pmids":["28978483"],"confidence":"High","gaps":["Whether enhancer fine-tuning requires catalytic versus scaffolding activity not separated","Cell-type-specific targets across neuronal subtypes not mapped"]},{"year":2018,"claim":"Discovery that HPV16 E6 promotes E6AP-mediated proteasomal degradation of KDM5C to activate EGFR/c-MET super-enhancers revealed a viral hijacking mechanism and positioned KDM5C as a constitutive enhancer repressor whose removal drives oncogene activation.","evidence":"Co-IP, protein stability assays, ChIP-seq, RNA-seq in cervical cancer cells","pmids":["29339538"],"confidence":"High","gaps":["Direct ubiquitylation sites on KDM5C by E6AP not mapped","Whether other viral oncoproteins similarly target KDM5C is unknown"]},{"year":2020,"claim":"Genetic epistasis between KDM5C and the H3K4 methyltransferase KMT2A — where double mutation rescues dendritic and behavioral deficits of single mutants — established that the balance of H3K4me writing and erasing, not absolute levels, governs neuronal morphology and behavior.","evidence":"Kmt2a/Kdm5c double-mutant mice with dendritic spine morphology, behavioral assays, H3K4me ChIP, and transcriptomics","pmids":["32483278"],"confidence":"High","gaps":["Which specific genomic loci are the critical targets of the writer-eraser balance is unknown","Whether pharmacological KMT2A inhibition can rescue KDM5C loss in a therapeutic setting not tested"]},{"year":2022,"claim":"Structural-functional dissection of the ARID, PHD1, and linker domains showed that ARID is required for nucleosome demethylation while PHD1 auto-inhibits DNA recognition until relieved by H3 tail binding, and that XLID mutations in these regions alter substrate specificity — resolving the intramolecular regulation of KDM5C catalysis.","evidence":"In vitro kinetic assays with purified nucleosomes, domain-deletion and XLID mutation analysis","pmids":["36495919"],"confidence":"High","gaps":["No cryo-EM or crystal structure of full-length KDM5C on a nucleosome exists","How PHD1 relief is coordinated with cofactor binding in vivo is unknown"]},{"year":2022,"claim":"KDM5C was shown to activate Xist by converting H3K4me2/3 to H3K4me1 at the Xist locus, a function conserved across therian and even monotreme orthologs but absent in the Y-linked paralog KDM5D, establishing KDM5C as a key initiator of X-chromosome inactivation.","evidence":"Kdm5c KO in female mESCs, ectopic expression in male mESCs, ChIP for H3K4me states, RNA FISH, cross-species complementation","pmids":["35545632"],"confidence":"High","gaps":["How KDM5C is specifically targeted to the Xist locus is not resolved","Whether other X-escapee demethylases contribute to Xist regulation is untested"]},{"year":2022,"claim":"Identification of TRIM11 as a K48-ubiquitin E3 ligase for KDM5C, whose loss stabilizes KDM5C and represses breast tumor growth, defined a second post-translational degradation axis (alongside E6AP) controlling KDM5C abundance and enhancer output.","evidence":"Co-IP, ubiquitination assays, ChIP-seq, animal xenograft model","pmids":["36192394"],"confidence":"High","gaps":["Specific lysine residues ubiquitylated by TRIM11 not mapped","Whether TRIM11 and E6AP compete for the same KDM5C degron is unknown"]},{"year":2024,"claim":"KDM5C was found to directly control WNT signaling during a critical neurodevelopmental window, and transient WNT inhibition rescued transcriptomic, chromatin, and behavioral phenotypes in patient iPSCs and KO mice, identifying a druggable pathway downstream of KDM5C loss.","evidence":"Patient iPSC-derived neurons, Kdm5c KO mice, transcriptomics, chromatin profiling, pharmacological WNT inhibitor rescue, behavioral assays","pmids":["38383780"],"confidence":"High","gaps":["Direct target genes mediating KDM5C control of WNT components not fully catalogued","Whether the therapeutic window for WNT inhibition extends postnatally is unknown"]},{"year":2024,"claim":"Interaction with BRD4 revealed a reciprocal activation loop — KDM5C stimulates BRD4 enhancer recruitment while BRD4 stimulates KDM5C demethylase activity — explaining how KDM5C functions as an enhancer activator at certain loci despite its canonical repressor role, and creating vulnerability to BET inhibitors.","evidence":"Co-IP, ChIP-seq, in vitro demethylase assays, xenograft model, patient-derived organoids","pmids":["38285760"],"confidence":"High","gaps":["Whether BRD4 allosterically activates KDM5C or acts through an intermediary is unresolved","Genome-wide delineation of KDM5C repressor versus BRD4-dependent activator loci not complete"]},{"year":2024,"claim":"KDM5C scaffolds YY1 chromatin recruitment in a JmjC domain-dependent but catalytically independent manner, demonstrating a genetically separable non-enzymatic function and revealing synergistic lethality upon dual KDM5C/YY1 inhibition.","evidence":"Co-IP, ChIP-seq, RNA-seq, JmjC domain catalytic-dead mutant analysis, combinatorial knockdown","pmids":["39433896"],"confidence":"Medium","gaps":["The JmjC structural determinant recognized by YY1 is unknown","Whether catalytic-dead KDM5C retains all scaffolding functions beyond YY1 is untested","Synergistic lethality not validated in vivo"]},{"year":2024,"claim":"KDM5C was established as a regulator of immune cell identity: its deletion in dendritic cells alters cDC1/cDC2B ratios and antigen presentation, while reduced KDM5C in plasmacytoid DCs elevates IL-6 to promote pathogenic Th17 skewing in diabetic wounds.","evidence":"DC-specific Kdm5c conditional KO mice, flow cytometry, RNA-seq, Listeria infection; human diabetic tissue, murine wound models, cytokine and T-cell co-culture assays","pmids":["39052479","38912581"],"confidence":"Medium","gaps":["Direct KDM5C target genes in DCs governing lineage specification not identified","Whether KDM5C immune phenotypes are catalytic or scaffolding-dependent is unknown"]},{"year":2025,"claim":"KDM5C stabilizes CRBN independently of demethylase activity and enhances lenalidomide efficacy in AML, while also regulating Cxcl12 in bone marrow MSCs to control sex-biased hematopoietic niche function, expanding KDM5C's roles to non-catalytic protein stabilization and niche biology.","evidence":"TurboID proximity labeling, Co-IP, AML cell viability assays; MSC-specific Kdm5c KO mice, scRNA-seq, transplantation assays","pmids":["39881283","39836478"],"confidence":"Medium","gaps":["Mechanism by which KDM5C stabilizes CRBN not defined","Whether CRBN stabilization occurs in non-AML contexts is unknown","Cxcl12 regulation may be indirect"]},{"year":null,"claim":"A high-resolution structure of full-length KDM5C on a nucleosome substrate, systematic separation of catalytic versus scaffolding functions across cell types, and identification of the full spectrum of direct ubiquitylation sites and degron-E3 ligase interactions remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or crystal structure of KDM5C–nucleosome complex","Catalytic versus scaffold functions not genetically separated in most biological contexts","Complete map of post-translational modifications controlling KDM5C stability is lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,7,8,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,9,16,17]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,19]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[19,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[26,25]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,6,9,18]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[6]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,16,17]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,6,16,19]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,9,17,27]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[21,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[9,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[23,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,15]}],"complexes":["REST/CoREST/HDAC1/HDAC2/G9a complex","SUV39H1/HP1α/DDB1 heterochromatin complex"],"partners":["REST","HDAC1","G9A","BRD4","PCNA","TRIM11","YY1","CRBN"],"other_free_text":[]},"mechanistic_narrative":"KDM5C is an X-linked JmjC-domain histone demethylase that converts H3K4me3 to H3K4me2/me1 and serves as a major transcriptional regulator coupling histone modification erasure with gene silencing, enhancer regulation, heterochromatin maintenance, DNA replication, X-chromosome inactivation, and cell fate decisions across neuronal, immune, and metabolic lineages. Its catalytic activity on nucleosomes requires the ARID domain and is auto-inhibited by the PHD1 finger until engagement with the H3 tail, and it assembles into chromatin-regulatory complexes containing REST/HDAC1/HDAC2/G9a for neuronal gene repression, BRD4 for enhancer activation, and SUV39H1/HP1α for heterochromatin integrity [PMID:17320160, PMID:17468742, PMID:36495919, PMID:38285760, PMID:26551685]. Beyond catalysis, KDM5C possesses demethylase-independent scaffolding functions, including promoting YY1 chromatin recruitment via its JmjC domain and stabilizing CRBN protein, and it regulates WNT signaling output during cortical neurogenesis such that transient WNT inhibition rescues neurodevelopmental phenotypes in KDM5C-deficient models [PMID:39433896, PMID:39881283, PMID:38383780]. Loss-of-function mutations in KDM5C cause X-linked intellectual disability, with patient missense mutations reducing protein stability, enzymatic activity, or substrate specificity [PMID:25666439, PMID:19826449, PMID:36495919]."},"prefetch_data":{"uniprot":{"accession":"P41229","full_name":"Lysine-specific demethylase 5C","aliases":["Histone demethylase JARID1C","Jumonji/ARID domain-containing protein 1C","Protein SmcX","Protein Xe169","[histone H3]-trimethyl-L-lysine(4) demethylase 5C"],"length_aa":1560,"mass_kda":175.7,"function":"Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code (PubMed:28262558). Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Participates in transcriptional repression of neuronal genes by recruiting histone deacetylases and REST at neuron-restrictive silencer elements. 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Multiforme.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36142158","citation_count":9,"is_preprint":false},{"pmid":"36831303","id":"PMC_36831303","title":"Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase KDM5C.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36831303","citation_count":9,"is_preprint":false},{"pmid":"33654410","id":"PMC_33654410","title":"KDM5C Expedites Lung Cancer Growth and Metastasis Through Epigenetic Regulation of MicroRNA-133a.","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33654410","citation_count":9,"is_preprint":false},{"pmid":"37657612","id":"PMC_37657612","title":"The X-linked histone demethylases KDM5C and KDM6A as regulators of T cell-driven autoimmunity in the central nervous system.","date":"2023","source":"Brain research 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experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic reconstitution with mechanistic follow-up, replicated across multiple family members, validated in vivo\",\n      \"pmids\": [\"17320160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A KDM5C-containing complex isolated from HeLa cells includes the histone deacetylases HDAC1 and HDAC2, the H3K9 methyltransferase G9a, and the transcriptional repressor REST; KDM5C and REST co-occupy neuron-restrictive silencing elements in promoters of REST target genes (SCN2A, SYN1), and KDM5C depletion derepresses these targets while increasing H3K4me3 at their promoters.\",\n      \"method\": \"Complex purification from HeLa cells, reciprocal co-immunoprecipitation, ChIP, RNAi-mediated knockdown with transcriptional and histone modification readouts\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP, and functional derepression assay in a single study\",\n      \"pmids\": [\"17468742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"KDM5C requires multiple functional domains for H3K4me3 demethylase activity, can form homomers through amino acids 204–493, and physically interacts with Smad3; overexpression of KDM5C inhibits Smad3-mediated transcriptional activation, acting as a Smad3 corepressor.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion mutagenesis, reporter gene transcription assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP and reporter assay, single lab\",\n      \"pmids\": [\"18078810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PCNA is required for loading KDM5C onto chromatin; KDM5C contains a PIP box motif, and mutation of PIP box residues disrupts KDM5C–PCNA interaction and reduces the chromatin-bound fraction of KDM5C.\",\n      \"method\": \"siRNA knockdown of PCNA, site-directed mutagenesis of PIP box, chromatin fractionation\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis combined with fractionation, but single lab\",\n      \"pmids\": [\"21996408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ARX directly regulates KDM5C expression by binding a conserved noncoding element in its regulatory region; polyalanine-expansion mutations in ARX reduce binding to this element and decrease KDM5C mRNA levels, which in turn reduces KDM5C protein and leads to increased H3K4me3 and failure to repress downstream neuronal targets (Scn2a, Syn1, Bdnf).\",\n      \"method\": \"Reporter assays, quantitative RT-PCR in Arx-KO cells, ChIP, chromatin immunoprecipitation, in vitro neuronal differentiation\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (reporter, ChIP, qRT-PCR) in single lab\",\n      \"pmids\": [\"23246292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KDM5C is required for proper DNA replication at early origins; KDM5C demethylates H3K4me3 to drive the assembly of the pre-initiation complex, facilitating chromatin binding of CDC45 and PCNA, and its knockdown impairs replication origin firing without affecting fork activation or H4 acetylation.\",\n      \"method\": \"siRNA knockdown, ChIP, DNA replication assays, measurement of pre-initiation complex protein chromatin binding\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic epistasis shown by knockdown with multiple chromatin and replication readouts, single lab\",\n      \"pmids\": [\"25712104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KDM5C localizes on heterochromatin (characterized by H3K9me3), is required for heterochromatin replication, and forms a complex with SUV39H1, HP1α, and the CUL4 complex adaptor DDB1; KDM5C inactivation leads to derepression of heterochromatic noncoding RNAs, triggering genomic instability.\",\n      \"method\": \"ChIP-seq, Co-immunoprecipitation, knockdown with ncRNA expression and genomic instability readouts, ccRCC patient sample analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP-seq, Co-IP, functional knockdown, patient validation) supporting mechanism\",\n      \"pmids\": [\"26551685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Patient-associated KDM5C missense mutations (P480L, D402Y) reduce protein stability and enzymatic demethylase activity; a start-codon mutation (c.2T>C) causes production of an N-terminally truncated protein lacking detectable demethylase activity; a frameshift (c.3223delG) leads to complete protein loss; patient fibroblasts show upregulation of specific target genes consistent with local chromatin changes.\",\n      \"method\": \"Primary patient cell biochemistry, in vitro demethylase activity assays, protein stability measurements, gene expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay combined with patient cell validation across multiple mutations\",\n      \"pmids\": [\"25666439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KDM5C patient mutation P554T compromises both tri- and di-demethylase activity in functional assays.\",\n      \"method\": \"In vitro demethylase activity assay on recombinant protein carrying patient mutations\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 method — in vitro assay, but single mutation in single study\",\n      \"pmids\": [\"19826449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Kdm5c acts in neurons as a transcriptional repressor responsible for developmental silencing of germline genes during cellular differentiation and for fine-tuning activity-regulated enhancers during neuronal maturation; in adult neurons it prevents incorrect activation of non-neuronal and cryptic promoters.\",\n      \"method\": \"Kdm5c-null and forebrain-restricted inducible knockout mice; parallel behavioral, transcriptomic, and epigenomic analyses; chromatin accessibility and gene expression assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple orthogonal omics readouts and functional assays in vivo\",\n      \"pmids\": [\"28978483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HPV16 E6 oncoprotein physically interacts with KDM5C and promotes its degradation in an E6AP E3 ligase- and proteasome-dependent manner; KDM5C degradation activates super-enhancers of EGFR and c-MET by modulating H3K4me3/H3K4me1 dynamics and increasing bidirectional enhancer RNA transcription.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assays, ChIP-seq, RNA-seq, gain/loss-of-function in cervical cancer cells\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, proteomics, genome-wide ChIP-seq, and RNA-seq with mechanistic follow-up\",\n      \"pmids\": [\"29339538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KDM5C-R1115H mutation does not affect enzymatic activity or protein stability but fails to fully suppress target gene expression in post-mitotic neurons and alters expression of a distinct gene set compared to wild-type, suggesting KDM5C has non-enzymatic roles in gene regulation.\",\n      \"method\": \"Enzymatic activity assays, protein stability measurements, overexpression in primary neurons with transcriptomic readout\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assays in neurons with transcriptomic readout, single lab\",\n      \"pmids\": [\"29670509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression at its promoter and compete for recruitment of PHF8; functional mutations in ARX, ZNF711, and PHF8 reduce KDM5C transcriptional activity, and this reduction correlates with severity of neurodevelopmental phenotype and elevated H3K4me3 at downstream targets (Scn2a, Syn1, Bdnf).\",\n      \"method\": \"KDM5C promoter reporter assays, ChIP, qRT-PCR in Arx-KO murine ES-derived neurons, C. elegans alr-1 rescue experiments with SAHA\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple reporter and ChIP experiments, cross-species validation, single lab\",\n      \"pmids\": [\"31691806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Functional interactions between the H3K4me writer KMT2A and the H3K4me eraser KDM5C are mutually suppressive: double mutation of Kmt2a and Kdm5c in mice reverses dendritic morphology deficits, key behavioral traits (including aggression), and partially corrects altered H3K4me landscapes seen in single mutants.\",\n      \"method\": \"Double-mutant mouse epistasis, dendritic spine morphology, behavioral assays, H3K4me ChIP, transcriptomics\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with multiple orthogonal readouts\",\n      \"pmids\": [\"32483278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kdm5c gene dosage (as an X-chromosome escapee) influences chromatin accessibility, gene expression in preadipocytes (including extracellular matrix remodeling genes), and adipocyte differentiation; modulating Kdm5c dosage in female mice to male levels reduces body weight, fat content, and food intake.\",\n      \"method\": \"ATAC-seq, RNA-seq in cultured preadipocytes; in vivo Kdm5c heterozygous and hemizygous mouse models with body composition measurements\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo experiments with genome-wide readouts and physiological phenotyping\",\n      \"pmids\": [\"32701509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM5C deficiency in ccRCC cells reprograms glycogen metabolism by upregulating HIF-related genes and G6PD (via loss of H3K4 demethylase activity at their promoters), directing glucose flux to the pentose phosphate pathway and increasing NADPH/GSH to confer resistance to ferroptosis.\",\n      \"method\": \"RNA-seq, metabolomics, heavy isotope tracer analysis, ChIP, CRISPR-Cas9 Kdm5c-knockout mice, xenograft models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with ChIP, metabolic tracing, in vivo KO validation\",\n      \"pmids\": [\"34522206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM5C acts as a transcriptional repressor at promoters through its H3K4me3 demethylase activity; KDM5C knockdown results in globally increased H3K4me3 and upregulation of bivalently marked immature genes, producing a de-differentiation phenotype in AML cells both in vitro and in vivo.\",\n      \"method\": \"In vivo shRNA screen, ChIP-seq, RNA-seq, murine and human AML cell lines and mouse models\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo screen combined with genome-wide ChIP-seq and transcriptomics with functional phenotype\",\n      \"pmids\": [\"36631623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM5C binds to active enhancers and recruits the P-TEFb complex to activate ERα-target genes, while also inhibiting TBK1 phosphorylation in the cytosol to repress type I interferons and ISGs; ZMYND8 is involved in both processes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, RNA-seq, kinase phosphorylation assays in breast cancer cells\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq and Co-IP with functional assays, but dual activator/repressor mechanism from single lab\",\n      \"pmids\": [\"33977073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KDM5C activates Xist lncRNA expression by converting H3K4me2/3 to H3K4me1 at the Xist locus; Kdm5c ablation significantly reduces Xist RNA in female cells; ectopic expression of mouse/human KDM5C (but not Y-linked KDM5D) induces Xist in male mESCs, and this function is conserved in marsupial and even monotreme KDM5C orthologs.\",\n      \"method\": \"Kdm5c knockout in female mESCs, ectopic expression in male mESCs, ChIP for H3K4 methylation states, RNA FISH for Xist, cross-species functional comparison\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — genetic KO with molecular readout, gain-of-function validation, cross-species conservation tested\",\n      \"pmids\": [\"35545632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The ARID domain of KDM5C is required for efficient nucleosome demethylation, while the PHD1 domain has an inhibitory role in KDM5C catalysis by inhibiting DNA recognition; the unstructured linker between ARID and PHD1 interacts with PHD1 and is necessary for nucleosome binding; XLID mutations adjacent to these domains enhance DNA binding and reduce substrate specificity.\",\n      \"method\": \"In vitro binding and kinetic studies with purified nucleosomes, domain-deletion mutagenesis, XLID mutation analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with nucleosomes, kinetic assays, mutagenesis\",\n      \"pmids\": [\"36495919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM11 is an E3 ubiquitin ligase for KDM5C that interacts with KDM5C, catalyzes K48-linked ubiquitin chains on KDM5C, and promotes its proteasomal degradation; TRIM11 deficiency stabilizes KDM5C and represses breast tumor growth; KDM5C and TRIM11 regulate MCAM enhancer activity through H3K4me3 modulation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, in vivo animal model, ChIP-seq, RNA-seq\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assay, in vivo validation, ChIP-seq\",\n      \"pmids\": [\"36192394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5C directly controls WNT signaling output during a specific developmental window to regulate the timely transition of primary to intermediate progenitor cells and neurogenesis; KDM5C depletion dysregulates canonical WNT pathway, and transient WNT inhibition rescues transcriptomic and chromatin landscapes in patient-derived iPSCs and behavioral changes in Kdm5c knockout mice.\",\n      \"method\": \"Patient iPSC-derived neurons, Kdm5c KO mice, transcriptomics, chromatin profiling, WNT modulator rescue experiments, behavioral assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro patient iPSC and in vivo mouse KO with transcriptomic, chromatin, and behavioral rescue, replicated\",\n      \"pmids\": [\"38383780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5C interacts with BRD4 and stimulates BRD4 enhancer recruitment; conversely, the BRD4 C-terminus binding to KDM5C stimulates KDM5C H3K4 demethylase activity; the abundance of KDM5C-associated BRD4 and H3K4me1/3 determines transcriptional activation of oncogenes; KDM5C depletion reduces BRD4 chromatin enrichment and enhances BET inhibitor efficacy.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, in vitro demethylase activity assays, xenograft mouse model, patient-derived organoids\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ChIP-seq, in vitro activity assay, in vivo validation, patient organoids\",\n      \"pmids\": [\"38285760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KDM5C regulates dendritic cell (DC) population heterogeneity and function; KDM5C-deficient DCs show increased inflammatory gene expression, altered lineage-specific gene expression, and decreased antigen presentation by cDC1s; the effect on cDC2B and cDC1 proportions is partly dependent on type I IFN and pDCs.\",\n      \"method\": \"DC-specific Kdm5c conditional KO mice, flow cytometry, RNA-seq, Listeria infection model with CD8 T cell response readout\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple cellular and transcriptomic readouts, single lab\",\n      \"pmids\": [\"39052479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Decreased KDM5C expression in diabetic plasmacytoid dendritic cells increases IL-6 transcription, which skews naive CD4+ T cells toward a Th17 phenotype; this process is regulated upstream by an IFN-I/TYK2/JAK1,3 signaling pathway; inhibiting KDM5C in non-diabetic wound pDCs mimics the diabetic Th17-skewing phenotype.\",\n      \"method\": \"Human tissue and murine wound healing models, genetic inhibition/overexpression, cytokine measurements, T cell co-culture assays, pathway inhibitor experiments\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model and human tissue with mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"38912581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KDM5C interacts with CRBN (cereblon) and stabilizes CRBN protein in an enzyme activity-independent manner, thereby enhancing the antileukemia effect of lenalidomide in AML cells.\",\n      \"method\": \"TurboID proximity labeling, quantitative proteomics, Co-immunoprecipitation, cell viability assays in AML lines and primary cells, KDM5C inhibitors\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling proteomics and Co-IP with functional validation, single lab\",\n      \"pmids\": [\"39881283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YY1 interacts with KDM5C, and KDM5C promotes global YY1 chromatin recruitment especially at promoters in a manner requiring an intact KDM5C JmjC domain but not its demethylase catalytic activity; dual inhibition of KDM5C and YY1 is synergistically lethal and increases transcriptional repression of cell cycle- and apoptosis-related genes.\",\n      \"method\": \"Protein interaction screen, Co-immunoprecipitation, ChIP-seq, RNA-seq, genetic knockdown, domain mutants\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, ChIP-seq, and transcriptomics with domain mutant mechanistic follow-up, single lab\",\n      \"pmids\": [\"39433896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KDM5C suppresses miR-320a transcription by directly binding to the miR-320a promoter to prevent histone H3K4 methylation; KITLG, an essential gene for ovarian development, is a direct target of miR-320a and is downregulated in 45,X gonadal tissues where KDM5C dosage is reduced.\",\n      \"method\": \"ChIP, in vitro promoter binding, miRNA/target validation assays, expression analysis in Turner syndrome (45,X) samples\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with functional promoter binding, multi-sample validation, single lab\",\n      \"pmids\": [\"27896428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In male bone marrow mesenchymal stromal cells (MSCs), lower Kdm5c expression leads to increased Cxcl12 expression; MSC-specific Kdm5c knockout in female mice increases MSC quantity and function, enhancing hematopoietic engraftment to male levels.\",\n      \"method\": \"Single-cell RNA-seq, MSC-specific Kdm5c KO mice, bone marrow transplantation assays, co-culture experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with in vivo functional readout, scRNA-seq, single lab\",\n      \"pmids\": [\"39836478\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KDM5C is an X-linked histone H3K4me2/3 demethylase whose JmjC catalytic domain reverses H3K4me3 to H3K4me2/me1; its activity is modulated by accessory domains (ARID required for nucleosome demethylation; PHD1 inhibitory, relieved by H3 tail engagement), by cofactor interactions (REST/HDAC1/HDAC2/G9a complex for neuronal gene silencing; BRD4 for enhancer regulation; PCNA for chromatin loading), and by post-translational control (TRIM11-mediated K48-ubiquitylation and proteasomal degradation; HPV E6-triggered E6AP-dependent degradation); KDM5C plays essential roles in transcriptional repression of neuronal and germline genes, activation of Xist for X-inactivation, regulation of heterochromatin integrity, DNA replication origin firing, WNT-controlled neurogenesis timing, and immune cell function, with loss-of-function causing X-linked intellectual disability and multiple cancer-associated phenotypes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KDM5C is an X-linked JmjC-domain histone demethylase that converts H3K4me3 to H3K4me2/me1 and serves as a major transcriptional regulator coupling histone modification erasure with gene silencing, enhancer regulation, heterochromatin maintenance, DNA replication, X-chromosome inactivation, and cell fate decisions across neuronal, immune, and metabolic lineages. Its catalytic activity on nucleosomes requires the ARID domain and is auto-inhibited by the PHD1 finger until engagement with the H3 tail, and it assembles into chromatin-regulatory complexes containing REST/HDAC1/HDAC2/G9a for neuronal gene repression, BRD4 for enhancer activation, and SUV39H1/HP1α for heterochromatin integrity [PMID:17320160, PMID:17468742, PMID:36495919, PMID:38285760, PMID:26551685]. Beyond catalysis, KDM5C possesses demethylase-independent scaffolding functions, including promoting YY1 chromatin recruitment via its JmjC domain and stabilizing CRBN protein, and it regulates WNT signaling output during cortical neurogenesis such that transient WNT inhibition rescues neurodevelopmental phenotypes in KDM5C-deficient models [PMID:39433896, PMID:39881283, PMID:38383780]. Loss-of-function mutations in KDM5C cause X-linked intellectual disability, with patient missense mutations reducing protein stability, enzymatic activity, or substrate specificity [PMID:25666439, PMID:19826449, PMID:36495919].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing KDM5C as an H3K4me3 demethylase and identifying its REST/HDAC1/HDAC2/G9a repressive complex resolved the molecular function and immediate chromatin context for KDM5C-mediated transcriptional silencing of neuronal genes.\",\n      \"evidence\": \"In vitro demethylase assays, peptide binding, complex purification from HeLa, reciprocal Co-IP, ChIP, and RNAi derepression of REST targets\",\n      \"pmids\": [\"17320160\", \"17468742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of KDM5C–REST complex assembly unknown\", \"Relative contribution of demethylase versus scaffold function not separated\", \"In vivo neuronal consequence of complex disruption not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying PCNA-dependent chromatin loading of KDM5C via a PIP box motif linked histone demethylation to the DNA replication machinery, later extended by the finding that KDM5C demethylates H3K4me3 at early origins to promote pre-initiation complex assembly and origin firing.\",\n      \"evidence\": \"PIP box mutagenesis with chromatin fractionation; siRNA knockdown with ChIP and DNA replication assays\",\n      \"pmids\": [\"21996408\", \"25712104\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KDM5C acts at all origins or a subset is unknown\", \"Direct physical contacts between KDM5C and pre-IC components beyond PCNA not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrating that KDM5C localizes to H3K9me3-marked heterochromatin in a complex with SUV39H1/HP1α/DDB1, and that its loss causes heterochromatic ncRNA derepression and genomic instability, established a tumor-suppressive role beyond euchromatic gene regulation.\",\n      \"evidence\": \"ChIP-seq, Co-IP, knockdown with ncRNA and instability readouts, ccRCC patient sample analysis\",\n      \"pmids\": [\"26551685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DDB1/CUL4 ubiquitylates a KDM5C substrate at heterochromatin is unknown\", \"Mechanism connecting ncRNA derepression to genomic instability not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Biochemical characterization of XLID-associated KDM5C mutations (P480L, D402Y, P554T, start-codon loss, frameshift) directly linked reduced demethylase activity or protein loss to disease, establishing the enzymatic basis of X-linked intellectual disability.\",\n      \"evidence\": \"In vitro demethylase assays on recombinant mutant proteins, patient fibroblast gene expression and protein stability measurements\",\n      \"pmids\": [\"25666439\", \"19826449\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Not all XLID mutations reduce catalytic activity — non-enzymatic pathogenic mechanisms remain unclear\", \"Structure–function relationship for most mutations not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional knockout in mouse forebrain neurons revealed that KDM5C silences germline genes during differentiation and fine-tunes activity-regulated enhancers during maturation, establishing its dual role as a developmental and experience-dependent chromatin regulator in neurons.\",\n      \"evidence\": \"Kdm5c-null and forebrain-specific inducible KO mice with parallel behavioral, transcriptomic, and epigenomic profiling\",\n      \"pmids\": [\"28978483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether enhancer fine-tuning requires catalytic versus scaffolding activity not separated\", \"Cell-type-specific targets across neuronal subtypes not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that HPV16 E6 promotes E6AP-mediated proteasomal degradation of KDM5C to activate EGFR/c-MET super-enhancers revealed a viral hijacking mechanism and positioned KDM5C as a constitutive enhancer repressor whose removal drives oncogene activation.\",\n      \"evidence\": \"Co-IP, protein stability assays, ChIP-seq, RNA-seq in cervical cancer cells\",\n      \"pmids\": [\"29339538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ubiquitylation sites on KDM5C by E6AP not mapped\", \"Whether other viral oncoproteins similarly target KDM5C is unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic epistasis between KDM5C and the H3K4 methyltransferase KMT2A — where double mutation rescues dendritic and behavioral deficits of single mutants — established that the balance of H3K4me writing and erasing, not absolute levels, governs neuronal morphology and behavior.\",\n      \"evidence\": \"Kmt2a/Kdm5c double-mutant mice with dendritic spine morphology, behavioral assays, H3K4me ChIP, and transcriptomics\",\n      \"pmids\": [\"32483278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific genomic loci are the critical targets of the writer-eraser balance is unknown\", \"Whether pharmacological KMT2A inhibition can rescue KDM5C loss in a therapeutic setting not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Structural-functional dissection of the ARID, PHD1, and linker domains showed that ARID is required for nucleosome demethylation while PHD1 auto-inhibits DNA recognition until relieved by H3 tail binding, and that XLID mutations in these regions alter substrate specificity — resolving the intramolecular regulation of KDM5C catalysis.\",\n      \"evidence\": \"In vitro kinetic assays with purified nucleosomes, domain-deletion and XLID mutation analysis\",\n      \"pmids\": [\"36495919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cryo-EM or crystal structure of full-length KDM5C on a nucleosome exists\", \"How PHD1 relief is coordinated with cofactor binding in vivo is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"KDM5C was shown to activate Xist by converting H3K4me2/3 to H3K4me1 at the Xist locus, a function conserved across therian and even monotreme orthologs but absent in the Y-linked paralog KDM5D, establishing KDM5C as a key initiator of X-chromosome inactivation.\",\n      \"evidence\": \"Kdm5c KO in female mESCs, ectopic expression in male mESCs, ChIP for H3K4me states, RNA FISH, cross-species complementation\",\n      \"pmids\": [\"35545632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How KDM5C is specifically targeted to the Xist locus is not resolved\", \"Whether other X-escapee demethylases contribute to Xist regulation is untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of TRIM11 as a K48-ubiquitin E3 ligase for KDM5C, whose loss stabilizes KDM5C and represses breast tumor growth, defined a second post-translational degradation axis (alongside E6AP) controlling KDM5C abundance and enhancer output.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ChIP-seq, animal xenograft model\",\n      \"pmids\": [\"36192394\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lysine residues ubiquitylated by TRIM11 not mapped\", \"Whether TRIM11 and E6AP compete for the same KDM5C degron is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"KDM5C was found to directly control WNT signaling during a critical neurodevelopmental window, and transient WNT inhibition rescued transcriptomic, chromatin, and behavioral phenotypes in patient iPSCs and KO mice, identifying a druggable pathway downstream of KDM5C loss.\",\n      \"evidence\": \"Patient iPSC-derived neurons, Kdm5c KO mice, transcriptomics, chromatin profiling, pharmacological WNT inhibitor rescue, behavioral assays\",\n      \"pmids\": [\"38383780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes mediating KDM5C control of WNT components not fully catalogued\", \"Whether the therapeutic window for WNT inhibition extends postnatally is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Interaction with BRD4 revealed a reciprocal activation loop — KDM5C stimulates BRD4 enhancer recruitment while BRD4 stimulates KDM5C demethylase activity — explaining how KDM5C functions as an enhancer activator at certain loci despite its canonical repressor role, and creating vulnerability to BET inhibitors.\",\n      \"evidence\": \"Co-IP, ChIP-seq, in vitro demethylase assays, xenograft model, patient-derived organoids\",\n      \"pmids\": [\"38285760\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether BRD4 allosterically activates KDM5C or acts through an intermediary is unresolved\", \"Genome-wide delineation of KDM5C repressor versus BRD4-dependent activator loci not complete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"KDM5C scaffolds YY1 chromatin recruitment in a JmjC domain-dependent but catalytically independent manner, demonstrating a genetically separable non-enzymatic function and revealing synergistic lethality upon dual KDM5C/YY1 inhibition.\",\n      \"evidence\": \"Co-IP, ChIP-seq, RNA-seq, JmjC domain catalytic-dead mutant analysis, combinatorial knockdown\",\n      \"pmids\": [\"39433896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The JmjC structural determinant recognized by YY1 is unknown\", \"Whether catalytic-dead KDM5C retains all scaffolding functions beyond YY1 is untested\", \"Synergistic lethality not validated in vivo\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"KDM5C was established as a regulator of immune cell identity: its deletion in dendritic cells alters cDC1/cDC2B ratios and antigen presentation, while reduced KDM5C in plasmacytoid DCs elevates IL-6 to promote pathogenic Th17 skewing in diabetic wounds.\",\n      \"evidence\": \"DC-specific Kdm5c conditional KO mice, flow cytometry, RNA-seq, Listeria infection; human diabetic tissue, murine wound models, cytokine and T-cell co-culture assays\",\n      \"pmids\": [\"39052479\", \"38912581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KDM5C target genes in DCs governing lineage specification not identified\", \"Whether KDM5C immune phenotypes are catalytic or scaffolding-dependent is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"KDM5C stabilizes CRBN independently of demethylase activity and enhances lenalidomide efficacy in AML, while also regulating Cxcl12 in bone marrow MSCs to control sex-biased hematopoietic niche function, expanding KDM5C's roles to non-catalytic protein stabilization and niche biology.\",\n      \"evidence\": \"TurboID proximity labeling, Co-IP, AML cell viability assays; MSC-specific Kdm5c KO mice, scRNA-seq, transplantation assays\",\n      \"pmids\": [\"39881283\", \"39836478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which KDM5C stabilizes CRBN not defined\", \"Whether CRBN stabilization occurs in non-AML contexts is unknown\", \"Cxcl12 regulation may be indirect\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of full-length KDM5C on a nucleosome substrate, systematic separation of catalytic versus scaffolding functions across cell types, and identification of the full spectrum of direct ubiquitylation sites and degron-E3 ligase interactions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cryo-EM or crystal structure of KDM5C–nucleosome complex\", \"Catalytic versus scaffold functions not genetically separated in most biological contexts\", \"Complete map of post-translational modifications controlling KDM5C stability is lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 7, 8, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 9, 16, 17]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 19]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [19, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [26, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 6, 9, 18]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 16, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 6, 16, 19]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 9, 17, 27]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [21, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [9, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [23, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 15]}\n    ],\n    \"complexes\": [\n      \"REST/CoREST/HDAC1/HDAC2/G9a complex\",\n      \"SUV39H1/HP1α/DDB1 heterochromatin complex\"\n    ],\n    \"partners\": [\n      \"REST\",\n      \"HDAC1\",\n      \"G9a\",\n      \"BRD4\",\n      \"PCNA\",\n      \"TRIM11\",\n      \"YY1\",\n      \"CRBN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}