Affinage

KDM5C

Lysine-specific demethylase 5C · UniProt P41229

Length
1560 aa
Mass
175.7 kDa
Annotated
2026-04-28
100 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2007 High

    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

    PMID:17320160 PMID:17468742

    Open questions at the time
    • 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
  2. 2011 Medium

    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

    PMID:21996408 PMID:25712104

    Open questions at the time
    • Whether KDM5C acts at all origins or a subset is unknown
    • Direct physical contacts between KDM5C and pre-IC components beyond PCNA not established
  3. 2015 High

    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

    PMID:26551685

    Open questions at the time
    • Whether DDB1/CUL4 ubiquitylates a KDM5C substrate at heterochromatin is unknown
    • Mechanism connecting ncRNA derepression to genomic instability not resolved
  4. 2015 High

    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

    PMID:19826449 PMID:25666439

    Open questions at the time
    • Not all XLID mutations reduce catalytic activity — non-enzymatic pathogenic mechanisms remain unclear
    • Structure–function relationship for most mutations not resolved at atomic level
  5. 2017 High

    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

    PMID:28978483

    Open questions at the time
    • Whether enhancer fine-tuning requires catalytic versus scaffolding activity not separated
    • Cell-type-specific targets across neuronal subtypes not mapped
  6. 2018 High

    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

    PMID:29339538

    Open questions at the time
    • Direct ubiquitylation sites on KDM5C by E6AP not mapped
    • Whether other viral oncoproteins similarly target KDM5C is unknown
  7. 2020 High

    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

    PMID:32483278

    Open questions at the time
    • 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
  8. 2022 High

    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

    PMID:36495919

    Open questions at the time
    • 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
  9. 2022 High

    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

    PMID:35545632

    Open questions at the time
    • How KDM5C is specifically targeted to the Xist locus is not resolved
    • Whether other X-escapee demethylases contribute to Xist regulation is untested
  10. 2022 High

    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

    PMID:36192394

    Open questions at the time
    • Specific lysine residues ubiquitylated by TRIM11 not mapped
    • Whether TRIM11 and E6AP compete for the same KDM5C degron is unknown
  11. 2024 High

    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

    PMID:38383780

    Open questions at the time
    • Direct target genes mediating KDM5C control of WNT components not fully catalogued
    • Whether the therapeutic window for WNT inhibition extends postnatally is unknown
  12. 2024 High

    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

    PMID:38285760

    Open questions at the time
    • 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
  13. 2024 Medium

    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

    PMID:39433896

    Open questions at the time
    • 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
  14. 2024 Medium

    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

    PMID:38912581 PMID:39052479

    Open questions at the time
    • Direct KDM5C target genes in DCs governing lineage specification not identified
    • Whether KDM5C immune phenotypes are catalytic or scaffolding-dependent is unknown
  15. 2025 Medium

    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

    PMID:39836478 PMID:39881283

    Open questions at the time
    • Mechanism by which KDM5C stabilizes CRBN not defined
    • Whether CRBN stabilization occurs in non-AML contexts is unknown
    • Cxcl12 regulation may be indirect

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0140110 transcription regulator activity 4 GO:0003677 DNA binding 2 GO:0042393 histone binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 3 GO:0005694 chromosome 1
Pathway
R-HSA-4839726 Chromatin organization 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-69306 DNA Replication 2
Partners
BRD4CRBNG9AHDAC1PCNARESTTRIM11YY1
Complex memberships
REST/CoREST/HDAC1/HDAC2/G9a complexSUV39H1/HP1α/DDB1 heterochromatin complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 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. In vitro histone demethylase assay, peptide binding assays, site-directed mutagenesis; zebrafish and primary neuron knockdown experiments Cell High 17320160
2007 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. Complex purification from HeLa cells, reciprocal co-immunoprecipitation, ChIP, RNAi-mediated knockdown with transcriptional and histone modification readouts Nature High 17468742
2007 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. Co-immunoprecipitation, domain-deletion mutagenesis, reporter gene transcription assays Biochemical and biophysical research communications Medium 18078810
2011 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. siRNA knockdown of PCNA, site-directed mutagenesis of PIP box, chromatin fractionation Epigenetics & chromatin Medium 21996408
2012 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). Reporter assays, quantitative RT-PCR in Arx-KO cells, ChIP, chromatin immunoprecipitation, in vitro neuronal differentiation American journal of human genetics Medium 23246292
2015 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. siRNA knockdown, ChIP, DNA replication assays, measurement of pre-initiation complex protein chromatin binding Nucleic acids research Medium 25712104
2015 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. ChIP-seq, Co-immunoprecipitation, knockdown with ncRNA expression and genomic instability readouts, ccRCC patient sample analysis The Journal of clinical investigation High 26551685
2015 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. Primary patient cell biochemistry, in vitro demethylase activity assays, protein stability measurements, gene expression analysis Human molecular genetics High 25666439
2015 KDM5C patient mutation P554T compromises both tri- and di-demethylase activity in functional assays. In vitro demethylase activity assay on recombinant protein carrying patient mutations European journal of human genetics Medium 19826449
2017 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. Kdm5c-null and forebrain-restricted inducible knockout mice; parallel behavioral, transcriptomic, and epigenomic analyses; chromatin accessibility and gene expression assays Cell reports High 28978483
2018 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. Co-immunoprecipitation, protein stability assays, ChIP-seq, RNA-seq, gain/loss-of-function in cervical cancer cells Cancer research High 29339538
2018 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. Enzymatic activity assays, protein stability measurements, overexpression in primary neurons with transcriptomic readout Frontiers in molecular neuroscience Medium 29670509
2019 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). KDM5C promoter reporter assays, ChIP, qRT-PCR in Arx-KO murine ES-derived neurons, C. elegans alr-1 rescue experiments with SAHA Human molecular genetics Medium 31691806
2020 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. Double-mutant mouse epistasis, dendritic spine morphology, behavioral assays, H3K4me ChIP, transcriptomics Communications biology High 32483278
2020 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. ATAC-seq, RNA-seq in cultured preadipocytes; in vivo Kdm5c heterozygous and hemizygous mouse models with body composition measurements The Journal of clinical investigation High 32701509
2021 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. RNA-seq, metabolomics, heavy isotope tracer analysis, ChIP, CRISPR-Cas9 Kdm5c-knockout mice, xenograft models Theranostics High 34522206
2021 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. In vivo shRNA screen, ChIP-seq, RNA-seq, murine and human AML cell lines and mouse models Leukemia High 36631623
2021 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. Co-immunoprecipitation, ChIP-seq, RNA-seq, kinase phosphorylation assays in breast cancer cells Advanced science Medium 33977073
2022 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. Kdm5c knockout in female mESCs, ectopic expression in male mESCs, ChIP for H3K4 methylation states, RNA FISH for Xist, cross-species functional comparison Nature communications High 35545632
2022 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. In vitro binding and kinetic studies with purified nucleosomes, domain-deletion mutagenesis, XLID mutation analysis Journal of molecular biology High 36495919
2022 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. Co-immunoprecipitation, ubiquitination assays, in vivo animal model, ChIP-seq, RNA-seq Cell death & disease High 36192394
2024 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. Patient iPSC-derived neurons, Kdm5c KO mice, transcriptomics, chromatin profiling, WNT modulator rescue experiments, behavioral assays Nature High 38383780
2024 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. Co-immunoprecipitation, ChIP-seq, in vitro demethylase activity assays, xenograft mouse model, patient-derived organoids Cancer research High 38285760
2024 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. DC-specific Kdm5c conditional KO mice, flow cytometry, RNA-seq, Listeria infection model with CD8 T cell response readout Cell reports Medium 39052479
2024 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. Human tissue and murine wound healing models, genetic inhibition/overexpression, cytokine measurements, T cell co-culture assays, pathway inhibitor experiments JCI insight Medium 38912581
2025 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. TurboID proximity labeling, quantitative proteomics, Co-immunoprecipitation, cell viability assays in AML lines and primary cells, KDM5C inhibitors Cellular & molecular biology letters Medium 39881283
2024 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. Protein interaction screen, Co-immunoprecipitation, ChIP-seq, RNA-seq, genetic knockdown, domain mutants EMBO reports Medium 39433896
2016 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. ChIP, in vitro promoter binding, miRNA/target validation assays, expression analysis in Turner syndrome (45,X) samples Human genetics Medium 27896428
2025 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. Single-cell RNA-seq, MSC-specific Kdm5c KO mice, bone marrow transplantation assays, co-culture experiments The Journal of clinical investigation Medium 39836478

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell 550 17320160
2007 The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature 355 17468742
2004 Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. American journal of human genetics 311 15586325
2019 The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism. Experimental & molecular medicine 188 31221981
2013 Clinical and pathological impact of VHL, PBRM1, BAP1, SETD2, KDM6A, and JARID1c in clear cell renal cell carcinoma. Genes, chromosomes & cancer 113 24166983
2008 A novel mutation in JARID1C/SMCX in a patient with autism spectrum disorder (ASD). American journal of medical genetics. Part A 110 18203167
2008 Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain. PloS one 107 18596936
2006 Novel JARID1C/SMCX mutations in patients with X-linked mental retardation. Human mutation 96 16541399
2017 Loss of Kdm5c Causes Spurious Transcription and Prevents the Fine-Tuning of Activity-Regulated Enhancers in Neurons. Cell reports 91 28978483
2021 Deficiency of the X-inactivation escaping gene KDM5C in clear cell renal cell carcinoma promotes tumorigenicity by reprogramming glycogen metabolism and inhibiting ferroptosis. Theranostics 89 34522206
2020 X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity. The Journal of clinical investigation 85 32701509
2013 Multilocus loss of DNA methylation in individuals with mutations in the histone H3 lysine 4 demethylase KDM5C. BMC medical genomics 78 23356856
2008 Mutations in JARID1C are associated with X-linked mental retardation, short stature and hyperreflexia. Journal of medical genetics 76 18697827
2008 Escape from X chromosome inactivation is an intrinsic property of the Jarid1c locus. Proceedings of the National Academy of Sciences of the United States of America 73 18971342
1994 Isolation and characterization of XE169, a novel human gene that escapes X-inactivation. Human molecular genetics 72 8162017
2018 E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone Demethylase KDM5C. Cancer research 62 29339538
2015 Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. The Journal of clinical investigation 62 26551685
2006 A novel mutation in JARID1C gene associated with mental retardation. European journal of human genetics : EJHG 61 16538222
2015 Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity. Human molecular genetics 60 25666439
1996 Tissue and lineage-specific variation in inactive X chromosome expression of the murine Smcx gene. Human molecular genetics 57 8872478
2018 Altered Gene-Regulatory Function of KDM5C by a Novel Mutation Associated With Autism and Intellectual Disability. Frontiers in molecular neuroscience 53 29670509
2015 H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing. Nucleic acids research 52 25712104
2018 Peripheral blood epi-signature of Claes-Jensen syndrome enables sensitive and specific identification of patients and healthy carriers with pathogenic mutations in KDM5C. Clinical epigenetics 51 29456765
2009 Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype-phenotype correlation. European journal of human genetics : EJHG 51 19826449
1996 The mouse Smcx gene exhibits developmental and tissue specific variation in degree of escape from X inactivation. Human molecular genetics 51 8872477
2021 The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 50 33977073
1997 Analysis of mutation rates in the SMCY/SMCX genes shows that mammalian evolution is male driven. Mammalian genome : official journal of the International Mammalian Genome Society 49 9060413
2011 A novel nonsense mutation in KDM5C/JARID1C gene causing intellectual disability, short stature and speech delay. Neuroscience letters 47 21575681
2014 KDM5C mutational screening among males with intellectual disability suggestive of X-Linked inheritance and review of the literature. European journal of medical genetics 46 24583395
1994 The murine Xe169 gene escapes X-inactivation like its human homologue. Nature genetics 45 7951318
2015 Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders. European journal of human genetics : EJHG 43 26059843
2020 Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation. Communications biology 42 32483278
2020 LncRNA LOXL1-AS1 is transcriptionally activated by JUND and contributes to osteoarthritis progression via targeting the miR-423-5p/KDM5C axis. Life sciences 38 32679142
2012 A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX. American journal of human genetics 38 23246292
2007 Repression of Smad3 activity by histone demethylase SMCX/JARID1C. Biochemical and biophysical research communications 38 18078810
2019 KDM5C is transcriptionally regulated by BRD4 and promotes castration-resistance prostate cancer cell proliferation by repressing PTEN. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 37 30921702
2020 Further delineation of the female phenotype with KDM5C disease causing variants: 19 new individuals and review of the literature. Clinical genetics 36 32279304
2012 A novel c.2T > C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability. European journal of medical genetics 36 22326837
2020 KDM5C Represses FASN-Mediated Lipid Metabolism to Exert Tumor Suppressor Activity in Intrahepatic Cholangiocarcinoma. Frontiers in oncology 35 32714863
2015 Histone demethylase JARID1C promotes breast cancer metastasis cells via down regulating BRMS1 expression. Biochemical and biophysical research communications 35 26182878
2022 Activation of Xist by an evolutionarily conserved function of KDM5C demethylase. Nature communications 34 35545632
2016 Enhancement of Proliferation and Invasion of Gastric Cancer Cell by KDM5C Via Decrease in p53 Expression. Technology in cancer research & treatment 33 26858085
2018 KDM5c inhibits multidrug resistance of colon cancer cell line by down-regulating ABCC1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 32 30257334
2015 Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features. European journal of medical genetics 32 25858702
2014 SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter. Virology 30 25222147
2021 Relationship between visceral adipose tissue and genetic mutations (VHL and KDM5C) in clear cell renal cell carcinoma. La Radiologia medica 27 33400184
2020 Histone Lysine Demethylases KDM5B and KDM5C Modulate Genome Activation and Stability in Porcine Embryos. Frontiers in cell and developmental biology 27 32211412
2020 KDM5c Promotes Colon Cancer Cell Proliferation Through the FBXW7-c-Jun Regulatory Axis. Frontiers in oncology 26 33042830
2019 Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders. Human molecular genetics 26 31691806
2024 WNT signalling control by KDM5C during development affects cognition. Nature 23 38383780
2018 Physiological effects of KDM5C on neural crest migration and eye formation during vertebrate development. Epigenetics & chromatin 23 30522514
2021 Molecular and cellular events linking variants in the histone demethylase KDM5C to the intellectual disability disorder Claes-Jensen syndrome. The FEBS journal 22 34536985
2016 Patient Mutations of the Intellectual Disability Gene KDM5C Downregulate Netrin G2 and Suppress Neurite Growth in Neuro2a Cells. Journal of molecular neuroscience : MN 22 27421841
2021 Human umbilical cord mesenchymal stem cells-derived exosomal microRNA-181a retards nasopharyngeal carcinoma development by mediating KDM5C. Journal of cancer research and clinical oncology 21 34218325
2022 Histone Demethylase KDM5C Drives Prostate Cancer Progression by Promoting EMT. Cancers 20 35454801
2021 Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures. Genes 20 34356104
2015 Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease. International journal of molecular sciences 20 26580603
2023 The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes. Leukemia 19 36631623
2020 E6 hijacks KDM5C/lnc_000231/miR-497-5p/CCNE1 axis to promote cervical cancer progression. Journal of cellular and molecular medicine 19 32818316
2020 Mutations of histone demethylase genes encoded by X and Y chromosomes, Kdm5c and Kdm5d, lead to noncompaction cardiomyopathy in mice. Biochemical and biophysical research communications 18 32081420
2022 Alcohol-associated fibrosis in females is mediated by female-specific activation of lysine demethylases KDM5B and KDM5C. Hepatology communications 17 35468265
2022 Regulation of KDM5C stability and enhancer reprogramming in breast cancer. Cell death & disease 17 36192394
2016 XCI-escaping gene KDM5C contributes to ovarian development via downregulating miR-320a. Human genetics 17 27896428
2022 Expanding the genetics and phenotypic spectrum of Lysine-specific demethylase 5C (KDM5C): a report of 13 novel variants. European journal of human genetics : EJHG 16 36434256
2011 Proliferating cell nuclear antigen is required for loading of the SMCX/KMD5C histone demethylase onto chromatin. Epigenetics & chromatin 15 21996408
2022 E2F6/KDM5C promotes SF3A3 expression and bladder cancer progression through a specific hypomethylated DNA promoter. Cancer cell international 14 35248043
2021 Predictive Value of KDM5C Alterations for Immune Checkpoint Inhibitors Treatment Outcomes in Patients With Cancer. Frontiers in immunology 14 33953726
2012 Short-term memory deficits in carrier females with KDM5C mutations. Genetic counseling (Geneva, Switzerland) 14 22611640
2022 Mutations in KMT2C, BCOR and KDM5C Predict Response to Immune Checkpoint Blockade Therapy in Non-Small Cell Lung Cancer. Cancers 13 35681795
2021 microRNA-181a promotes the oncogene S100A2 and enhances papillary thyroid carcinoma growth by mediating the expression of histone demethylase KDM5C. Journal of endocrinological investigation 13 34143366
2020 ELK1 activated-long noncoding RNA LBX2-AS1 aggravates the progression of ovarian cancer through targeting miR-4784/KDM5C axis. Journal of molecular histology 13 33099720
2019 DNA methylation fingerprint of monozygotic twins and their singleton sibling with intellectual disability carrying a novel KDM5C mutation. European journal of medical genetics 12 31419599
2007 Backbone and sidechain 1H, 13C and 15N resonance assignments of the Bright/ARID domain from the human JARID1C (SMCX) protein. Biomolecular NMR assignments 12 19636912
2024 Histone demethylase JARID1C/KDM5C regulates Th17 cells by increasing IL-6 expression in diabetic plasmacytoid dendritic cells. JCI insight 11 38912581
2023 Exploration of Morphological Features of Clear Cell Renal Cell Carcinoma With PBRM1, SETD2, BAP1, or KDM5C Mutations. International journal of surgical pathology 11 36911986
2021 Caregiver-reported characteristics of children diagnosed with pathogenic variants in KDM5C. American journal of medical genetics. Part A 11 34089235
2022 Chromatin Sensing by the Auxiliary Domains of KDM5C Regulates Its Demethylase Activity and Is Disrupted by X-linked Intellectual Disability Mutations. Journal of molecular biology 10 36495919
2021 A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report. BMC neurology 10 34530748
2021 Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability. Neurology. Genetics 10 34877407
2019 The potential role of a retrotransposed gene and a long noncoding RNA in regulating an X-linked chromatin gene (KDM5C): Novel epigenetic mechanism in autism. Autism research : official journal of the International Society for Autism Research 10 31087518
2016 Different X-linked KDM5C mutations in affected male siblings: is maternal reversion error involved? Clinical genetics 10 26919706
2023 Sexually Dimorphic Alterations in the Transcriptome and Behavior with Loss of Histone Demethylase KDM5C. Cells 9 36831303
2023 The X-linked histone demethylases KDM5C and KDM6A as regulators of T cell-driven autoimmunity in the central nervous system. Brain research bulletin 9 37657612
2022 The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme. International journal of molecular sciences 9 36142158
2022 Elevated histone demethylase KDM5C increases recurrent miscarriage risk by preventing trophoblast proliferation and invasion. Cell death discovery 9 36550096
2021 KDM5C Expedites Lung Cancer Growth and Metastasis Through Epigenetic Regulation of MicroRNA-133a. OncoTargets and therapy 9 33654410
2024 Transcriptional programming mediated by the histone demethylase KDM5C regulates dendritic cell population heterogeneity and function. Cell reports 8 39052479
2022 Expanding the Spectrum of KDM5C Neurodevelopmental Disorder: A Novel De Novo Stop Variant in a Young Woman and Emerging Genotype-Phenotype Correlations. Genes 6 36553533
2021 HOXD3 Up-regulating KDM5C Promotes Malignant Progression of Diffuse Large B-Cell Lymphoma by Decreasing p53 Expression. Balkan medical journal 6 34928233
2016 Cofactors-loaded quaternary structure of lysine-specific demethylase 5C (KDM5C) protein: Computational model. Proteins 6 27696497
2025 Sexual dimorphism in the mouse bone marrow niche regulates hematopoietic engraftment via sex-specific Kdm5c/Cxcl12 signaling. The Journal of clinical investigation 5 39836478
2024 KDM5C-Mediated Recruitment of BRD4 to Chromatin Regulates Enhancer Activation and BET Inhibitor Sensitivity. Cancer research 5 38285760
2023 PBRM1 and KDM5C cooperate to define high-angiogenesis tumors and increased antiangiogenic response in renal cancer. American journal of cancer research 5 37293154
2022 A female case with novel KDM5C heterozygous variation presenting with Claes-Jensen type-like phonotype. BMC neurology 5 36536324
2021 X-linked mental retardation and severe short stature with a novel mutation of the KDM5C gene. Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 5 33446955
2022 Contribution of DNA methylation profiling to the reclassification of a variant of uncertain significance in the KDM5C gene. European journal of medical genetics 4 35781022
2007 cDNA cloning, bioinformatic and tissue-specific expression analysis of porcine JARID1C gene. Journal of genetics and genomics = Yi chuan xue bao 4 18155621
2025 The histone demethylase KDM5C enhances the sensitivity of acute myeloid leukemia cells to lenalidomide by stabilizing cereblon. Cellular & molecular biology letters 3 39881283
2024 Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C. EMBO reports 3 39433896
2025 Multi-omics elucidation of KDM5C, KDM6A, and KMT2B roles in cancer epigenetic dysregulation and transcriptional reprogramming. Communications biology 2 41331063