Affinage

KDM5C

Lysine-specific demethylase 5C · UniProt P41229

Length
1560 aa
Mass
175.7 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDM5C (SMCX/JARID1C) is an X-linked JmjC-domain histone demethylase that reverses H3K4me3 to H3K4me2 and H3K4me1, with its catalytic output shaped by accessory domains: the ARID domain is required for efficient nucleosome demethylation while the PHD1 domain is inhibitory, and the N-terminal PHD finger reads H3K9me3 to couple H3K4 demethylation to repressive H3K9 methylation (PMID:17320160, PMID:36495919). Through this enzymatic activity KDM5C functions predominantly as a transcriptional repressor, assembling into a repressive complex with REST, HDAC1/2 and the H3K9 methyltransferase G9a at neuron-restrictive silencing elements (PMID:17468742) and associating with SUV39H1, HP1α and the CUL4 adaptor DDB1 on H3K9me3 heterochromatin, where it is required for heterochromatin replication and restraint of heterochromatic noncoding RNAs to preserve genomic stability (PMID:26551685). Chromatin loading depends on PCNA via a PIP-box motif, and KDM5C demethylates H3K4me3 at early replication origins to license pre-initiation complex assembly (PMID:21996408, PMID:25712104). In the nervous system KDM5C silences germline and cryptic non-neuronal promoters, fine-tunes activity-regulated enhancers, and times WNT signaling to control the progenitor-to-neuron transition, with loss causing neurodevelopmental and behavioral deficits (PMID:28978483, PMID:38383780); it operates as a mutually suppressive writer-eraser pair with the H3K4 methyltransferase KMT2A (PMID:32483278). KDM5C protein levels are controlled by K48-linked ubiquitination through the E3 ligase TRIM11 (PMID:36192394). Beyond repression, KDM5C exerts context-dependent activating and non-enzymatic roles: it recruits BRD4 to enhancers and is reciprocally stimulated by BRD4 to drive oncogene transcription (PMID:38285760), and it promotes genome-wide YY1 chromatin recruitment in a JmjC-dependent but demethylase-independent manner, with which it is synthetically lethal (PMID:39433896). KDM5C also governs X-inactivation by activating Xist (PMID:35545632), adipocyte and bone-marrow-niche sex differences (PMID:32701509, PMID:39836478), dendritic cell heterogeneity and antigen presentation (PMID:39052479), and metabolic reprogramming in clear cell renal carcinoma (PMID:34522206). Patient missense and start-codon mutations that reduce demethylase activity, protein stability, or H3K9me3 binding underlie X-linked intellectual disability (PMID:17320160, PMID:25666439, PMID:36495919).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2007 High

    Established KDM5C as a bona fide enzyme by showing it is a JmjC-domain demethylase that reverses H3K4me3/me2 and reads H3K9me3, defining its core molecular activity and linking patient mutations to lost function.

    Evidence In vitro demethylase assay, PHD-peptide binding, patient-variant mutagenesis in zebrafish and neurons

    PMID:17320160

    Open questions at the time
    • Mechanism coupling H3K4 demethylation to H3K9 methylation not resolved in vivo
    • No structural model of the catalytic apparatus
  2. 2007 High

    Defined the repressive complex context for KDM5C, answering how it represses genes by physically partnering REST, HDAC1/2 and G9a at NRSE promoters.

    Evidence Reciprocal Co-IP from HeLa extracts, ChIP, siRNA knockdown with RT-PCR/ChIP readout

    PMID:17468742

    Open questions at the time
    • Stoichiometry and assembly order of the complex unknown
    • Whether all targets require the full complex unaddressed
  3. 2008 High

    Showed that the Jarid1c locus escapes X-inactivation as an intrinsic DNA-sequence property, explaining its sex-biased dosage.

    Evidence Transgenic BAC integration into XX ES cells, allelic expression, RNA/DNA FISH

    PMID:18971342

    Open questions at the time
    • Sequence elements conferring escape within the 112-kb domain not pinpointed
  4. 2011 Medium

    Identified the mechanism of chromatin loading, showing a PIP-box mediates PCNA-dependent recruitment of KDM5C to chromatin.

    Evidence siRNA/chromatin fractionation, PIP-box mutagenesis, Co-IP

    PMID:21996408

    Open questions at the time
    • Single lab; PCNA dependence not validated genome-wide
    • Cell-cycle timing of loading unresolved
  5. 2012 Medium

    Placed KDM5C downstream of ARX in a transcriptional regulatory cascade controlling its own expression during neuronal differentiation.

    Evidence KDM5C promoter reporter, ARX ChIP, qRT-PCR in Arx-KO neural cells, H3K4me3 immunoblot

    PMID:23246292

    Open questions at the time
    • Direct vs indirect ARX effects on KDM5C protein not fully separated
  6. 2015 Medium

    Extended KDM5C function to DNA replication, demonstrating it demethylates H3K4me3 at origins to enable pre-initiation complex assembly and origin firing.

    Evidence siRNA knockdown, ChIP for CDC45/PCNA and histone marks, DNA fiber assay

    PMID:25712104

    Open questions at the time
    • Single lab
    • How origin specificity is achieved unknown
  7. 2015 High

    Defined a heterochromatin role, showing KDM5C complexes with SUV39H1/HP1α/DDB1 to support heterochromatin replication and suppress noncoding RNA-driven genomic instability in ccRCC.

    Evidence ChIP-seq, reciprocal Co-IP, shRNA/siRNA knockdown with ncRNA and rearrangement readouts

    PMID:26551685

    Open questions at the time
    • Whether genomic instability is enzymatic or scaffolding-dependent not resolved
  8. 2015 Medium

    Linked specific XLID patient alleles to defects in stability and catalysis, connecting molecular lesion to disease at the protein level.

    Evidence Demethylase activity and stability assays in patient fibroblasts, immunoblot, RNA-seq

    PMID:25666439

    Open questions at the time
    • Local rather than global expression changes; mechanism of locus selectivity unclear
  9. 2017 High

    Established the in vivo neuronal repressor function, showing KDM5C silences germline and cryptic promoters and tunes enhancers in mouse brain.

    Evidence Constitutive and conditional Kdm5c KO mice, RNA-seq, ChIP-seq, behavior

    PMID:28978483

    Open questions at the time
    • Direct target set vs secondary effects not fully separated
  10. 2018 Medium

    Revealed non-enzymatic gene-regulatory activity through an XLID mutation that retains catalysis yet fails to suppress a distinct gene set.

    Evidence Demethylase/stability assays plus neuronal overexpression with RNA-seq

    PMID:29670509

    Open questions at the time
    • Molecular basis of the non-enzymatic function not identified
  11. 2018 High

    Connected KDM5C to viral oncogenesis, showing HPV16 E6 drives its E6AP/proteasome-dependent degradation to derepress EGFR and c-MET super-enhancers.

    Evidence Co-IP, proteasome rescue, ChIP-seq, RNA-seq in cervical cancer cells

    PMID:25222147 PMID:29339538

    Open questions at the time
    • Degradation kinetics and E6 binding interface not mapped
  12. 2020 High

    Demonstrated KDM5C dosage drives sex differences in metabolism and a writer-eraser epistasis with KMT2A, framing physiological consequences of its enzymatic balance.

    Evidence ATAC-seq/RNA-seq with adipocyte differentiation and in vivo dosage models; Kmt2a/Kdm5c double-KO mice with morphology, behavior, ChIP-seq

    PMID:32483278 PMID:32701509

    Open questions at the time
    • Mechanism of dosage sensing in adipocytes unclear
    • Direct shared targets of the writer-eraser pair not enumerated
  13. 2022 High

    Resolved domain-level catalytic control, showing ARID promotes and PHD1 inhibits nucleosome demethylation and that XLID mutations distort DNA binding and specificity.

    Evidence In vitro nucleosome binding and kinetic demethylase assays, domain deletion, patient mutation analysis

    PMID:36495919

    Open questions at the time
    • No full-length structural model integrating all domains
  14. 2022 High

    Identified TRIM11 as the E3 ligase controlling KDM5C abundance via K48-linked ubiquitination, defining post-translational regulation of the enzyme.

    Evidence Co-IP, linkage-specific ubiquitination assay, ChIP at MCAM enhancer, TRIM11 KO model

    PMID:36192394

    Open questions at the time
    • Signals that trigger TRIM11-mediated turnover unknown
  15. 2022 High

    Showed KDM5C can act as an activator and a cytosolic immune regulator and that it activates Xist to enforce X-inactivation, broadening its functional repertoire beyond promoter repression.

    Evidence Co-IP (ZMYND8, P-TEFb), ChIP-seq, TBK1 phosphorylation assay; Kdm5c KO with Xist FISH and cross-species ectopic rescue

    PMID:26182878 PMID:33977073 PMID:35248043 PMID:35468265 PMID:35545632

    Open questions at the time
    • How activator vs repressor outcome is selected at a given locus unresolved
    • Cytosolic vs nuclear pool partitioning unclear
  16. 2023 High

    Defined KDM5C as a context-dependent tumor suppressor in AML, repressing bivalent immature genes to maintain differentiation.

    Evidence In vivo shRNA screen in Cebpa-mutant AML, ChIP-seq, RNA-seq, rescue of de-differentiation

    PMID:36631623

    Open questions at the time
    • Downstream mediators only partially defined
  17. 2024 High

    Connected KDM5C to a defined developmental signaling axis, showing it times WNT output to control neural progenitor transition, with WNT inhibition rescuing patient iPSC and mouse phenotypes.

    Evidence Patient iPSC differentiation, Kdm5c KO mice, RNA-seq/ATAC-seq, WNT modulation and in vivo WNT3A injection

    PMID:38383780

    Open questions at the time
    • Direct chromatin targets linking KDM5C to WNT genes not fully mapped
  18. 2024 High

    Established cooperative oncogenic partnerships, showing reciprocal stimulation with BRD4 at enhancers and demethylase-independent promotion of YY1 chromatin binding, both exploitable therapeutically.

    Evidence Co-IP, ChIP-seq, in vitro demethylase assays with BRD4, JmjC mutant analysis, double-KD viability, organoid/xenograft and BETi combination

    PMID:38285760 PMID:39433896

    Open questions at the time
    • Structural basis of BRD4 and YY1 interactions not determined
    • How JmjC enables YY1 recruitment without catalysis unknown
  19. 2024 High

    Defined immune-cell roles, showing KDM5C shapes dendritic cell heterogeneity and antigen presentation and restrains pDC inflammatory IL-6/Th17 output.

    Evidence DC-specific Kdm5c KO mice with flow cytometry, RNA-seq, Listeria challenge; pDC loss-of-function with T cell co-culture and pathway inhibitors

    PMID:38912581 PMID:39052479

    Open questions at the time
    • Direct chromatin targets in DC lineages not fully resolved
  20. 2025 High

    Extended physiological roles to the hematopoietic niche and refined ccRCC biology, establishing a Kdm5c-Cxcl12 axis driving sex differences and clarifying overlapping but distinct KDM5C/KDM5D programs with cross-rescue.

    Evidence MSC-specific Kdm5c KO, scRNA-seq, transplantation; CRISPR KDM5C/KDM5D ccRCC lines with ChIP-seq and xenograft; CRBN Co-IP and lenalidomide assays

    PMID:34522206 PMID:39836478 PMID:39881283 PMID:39955388

    Open questions at the time
    • Whether KDM5D regulation of shared genes is direct unresolved
    • CRBN stabilization mechanism characterized in a single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How KDM5C switches between repressive demethylase, transcriptional activator, and non-enzymatic scaffolding roles at a given locus, and the integrated structural basis of its multi-domain regulation, remain unresolved.
  • No full-length structure integrating ARID/PHD/JmjC domains
  • Rules governing activator vs repressor outcome unknown
  • Mechanism of demethylase-independent functions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0140110 transcription regulator activity 3 GO:0003677 DNA binding 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0042393 histone binding 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-1643685 Disease 3 R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2 R-HSA-69306 DNA Replication 2
Partners
BRD4G9AHDAC1HP1ΑPCNARESTSUV39H1YY1
Complex memberships
REST/HDAC1/2/G9a repressor complexSUV39H1/HP1α/DDB1 heterochromatin complex

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 SMCX/JARID1C (KDM5C) encodes a JmjC-domain histone demethylase that reverses H3K4me3 to H3K4me2 and H3K4me1, but not to unmethylated H3K4. The N-terminal PHD finger binds H3K9me3 peptides, suggesting coordination of H3K4 demethylation and H3K9 methylation in transcriptional repression. XLMR patient point mutations reduce demethylase activity or H3K9me3 binding. In vitro histone demethylase assay, PHD-peptide binding assay, mutagenesis of patient variants, zebrafish and primary neuron loss-of-function studies Cell High 17320160
2007 SMCX/JARID1C (KDM5C) forms a stable complex in HeLa cells with the histone deacetylases HDAC1 and HDAC2, the H3K9 methyltransferase G9a, and the transcriptional repressor REST. This complex co-occupies neuron-restrictive silencing elements (NRSEs) at REST target gene promoters (SCN2A, SYN1). siRNA-mediated KDM5C depletion derepresses these targets and increases H3K4me3 at their promoters. Co-immunoprecipitation from HeLa nuclear extracts, chromatin immunoprecipitation (ChIP), siRNA knockdown with RT-PCR and ChIP readout Nature High 17468742
2007 SMCX/KDM5C (an SMCX isoform) can reside predominantly in the cytoplasm yet retains H3K4me3 demethylase activity. KDM5C requires multiple functional domains for demethylase activity and forms homomers through amino acids 204–493. KDM5C physically interacts with Smad3 and overexpression of KDM5C inhibits Smad3-mediated transcriptional activation, making KDM5C a Smad3 co-repressor. Subcellular fractionation, in vitro demethylase assay, co-immunoprecipitation (KDM5C–Smad3 interaction), reporter gene transcription assay with overexpression Biochemical and biophysical research communications Medium 18078810
2008 The Jarid1c locus escapes X chromosome inactivation as an intrinsic property of its DNA sequence. Transgenic BACs carrying mouse Jarid1c integrated into normally X-inactivated regions still escaped X-inactivation, delimiting the escape domain to the 112-kb BAC overlap, independent of chromosomal position. Transgenic BAC integration into XX embryonic stem cells, allelic expression analysis, RNA/DNA FISH Proceedings of the National Academy of Sciences of the United States of America High 18971342
2011 KDM5C (SMCX) loading onto chromatin requires the protein PCNA. siRNA knockdown of PCNA reduced the chromatin-bound fraction of SMCX. A PCNA-interaction protein (PIP) box was identified in SMCX; site-directed mutagenesis of the PIP box residues abolished SMCX–PCNA association and SMCX chromatin binding. siRNA knockdown with chromatin fractionation, PIP-box identification, site-directed mutagenesis, co-immunoprecipitation Epigenetics & chromatin Medium 21996408
2012 ARX directly regulates KDM5C expression by binding a conserved noncoding element in the KDM5C regulatory region. PolyA-expansion mutations in ARX reduce trans-activation of KDM5C. Arx knockout in murine neural stem cells dramatically reduces Kdm5c mRNA, leading to decreased KDM5C protein and an inverse increase in H3K4me3 signal during neuronal differentiation. Reporter gene assay (KDM5C promoter), ChIP for ARX binding, quantitative RT-PCR in Arx-KO cells, H3K4me3 immunoblot American journal of human genetics Medium 23246292
2015 KDM5C/JARID1C is required for proper firing of early DNA replication origins. KDM5C demethylates H3K4me3 at origins to facilitate assembly of the pre-initiation complex, driving chromatin binding of CDC45 and PCNA; fork activation and histone H4 acetylation are not affected by KDM5C downregulation. siRNA knockdown, ChIP for replication proteins (CDC45, PCNA) and histone marks, DNA fiber assay for fork activation Nucleic acids research Medium 25712104
2015 JARID1C/KDM5C binds broadly to H3K9me3-marked heterochromatin, localizes on heterochromatin, is required for heterochromatin replication, and forms a complex with SUV39H1, HP1α, and the CUL4 adaptor DDB1. Loss of JARID1C in ccRCC cells causes unrestrained expression of heterochromatic noncoding RNAs, triggering genomic instability. ChIP-seq, co-immunoprecipitation (KDM5C–SUV39H1/HP1α/DDB1 complex), siRNA/shRNA knockdown with ncRNA expression and genomic rearrangement readouts The Journal of clinical investigation High 26551685
2015 Patient KDM5C missense mutations P480L and D402Y compromise protein stability and enzymatic demethylase activity, while a start-codon mutation (c.2T>C) leads to production of an N-terminally truncated protein lacking detectable demethylase activity. Patient fibroblasts show local changes in gene expression without global changes in histone methylation. Biochemical demethylase activity assay in patient cells, protein stability assays, immunoblot from primary fibroblasts, RNA-seq Human molecular genetics Medium 25666439
2017 Kdm5c acts as a transcriptional repressor responsible for developmental silencing of germline genes during neuronal differentiation and for fine-tuning activity-regulated enhancers during neuronal maturation. In adult neurons, Kdm5c prevents incorrect activation of non-neuronal and cryptic promoters. These roles were established using Kdm5c-null and forebrain-restricted inducible knockout mice with transcriptomic and epigenomic (ChIP-seq) analyses. Conditional and constitutive Kdm5c knockout mice, RNA-seq, ChIP-seq, behavioral 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. Ectopic KDM5C reduces H3K4me3 at super-enhancers of the EGFR and c-MET oncogenes, dampening enhancer RNA transcription and oncogene expression in HPV16-positive cervical cancer cells. Co-immunoprecipitation (E6–KDM5C), proteasome inhibitor rescue, ChIP-seq, RNA-seq, KDM5C overexpression in CaSki cells Cancer research High 29339538
2018 SMCX/KDM5C and components of the TIP60 complex contribute to HPV E2-mediated repression of the HPV LCR promoter. Di- and tri-methyl marks on H3K4 are reduced in the presence of E2 and SMCX, suggesting a mechanism by which SMCX demethylase activity mediates E2-dependent repression. ChIP for H3K4me2/3 marks at HPV LCR, siRNA knockdown, reporter assay Virology Medium 25222147
2018 A KDM5C mutation (R1115H) that does not affect enzymatic activity or protein stability nevertheless fails to fully suppress target gene expression when overexpressed in post-mitotic neurons and alters expression of a distinct gene set compared to wild-type KDM5C, indicating KDM5C has non-enzymatic roles in gene regulation. Demethylase activity assay, protein stability assay, overexpression in primary neurons with RNA-seq Frontiers in molecular neuroscience Medium 29670509
2019 KDM5C is regulated transcriptionally by a network of ARX, ZNF711, and PHF8: ARX and ZNF711 function as antagonistic transcription factors that activate KDM5C expression and compete for recruitment of PHF8 at the KDM5C promoter. In vitro promoter analysis and functional mutation studies show that severity of NDD phenotype correlates with reduction in KDM5C transcriptional activity. KDM5C promoter luciferase assay, ChIP for ARX/ZNF711/PHF8 binding, qRT-PCR in Arx-KO neurons, SAHA rescue experiments in C. elegans and mouse ES-derived neurons Human molecular genetics Medium 31691806
2020 KDM5C dosage, escaping X-inactivation, influences adipocyte chromatin accessibility, gene expression, and differentiation. In preadipocytes, KDM5C levels regulate extracellular matrix remodeling gene expression. Reducing Kdm5c gene dosage in XX female mice to XY male levels decreases body weight, fat content, and food intake. ATAC-seq, RNA-seq, in vitro adipocyte differentiation with KDM5C modulation, in vivo mouse model with Kdm5c dosage alteration The Journal of clinical investigation High 32701509
2020 KMT2A and KDM5C function as a mutually suppressive writer-eraser pair at H3K4: despite opposing enzymatic activities, double mutation of Kmt2a and Kdm5c in mice reverses dendritic spine reduction, aggression, and altered transcriptomes/H3K4me landscapes observed in each single mutant, demonstrating genetic epistasis between the writer and eraser. Double-knockout mouse model, dendritic morphology analysis, behavioral assays, RNA-seq, H3K4me ChIP-seq Communications biology High 32483278
2020 KDM5C attenuation in porcine embryos increases H3K9me1 on day 3 embryos and H3K4me1 on day 5 embryos (distinct from KDM5B), delays embryo genome activation, and impairs DNA double-strand break repair. Morpholino antisense knockdown in porcine embryos, histone methylation immunostaining, uridine incorporation assay, γH2AX staining for DSBs Frontiers in cell and developmental biology Medium 32211412
2021 KDM5C specifically demethylates H3K4me3 at the BRMS1 gene promoter, repressing BRMS1 transcription and thereby promoting breast cancer cell migration and invasion. BRMS1 knockdown reverses the migration inhibition caused by KDM5C silencing. siRNA knockdown, ChIP for H3K4me3 at BRMS1 promoter, migration/invasion assays, rescue experiment with BRMS1 siRNA Biochemical and biophysical research communications Medium 26182878
2021 KDM5C has dual activator and repressor activities: it binds active enhancers and recruits the P-TEFb complex to activate ERα-target genes; simultaneously it inhibits TBK1 phosphorylation in the cytosol to repress type I interferons. The co-factor ZMYND8 is involved in both processes. Co-immunoprecipitation (KDM5C–ZMYND8, KDM5C–P-TEFb), ChIP-seq, RNA-seq, TBK1 phosphorylation assay, KDM5C overexpression/KD Advanced science Medium 33977073
2021 KDM5C deficiency reprograms glycogen metabolism by specifically regulating HIF-related genes and G6PD (involved in glycogenesis/glycogenolysis and the pentose phosphate pathway) through its histone demethylase activity, thereby increasing NADPH/GSH and conferring resistance to ferroptosis in ccRCC cells. Heavy isotope tracer metabolic flux analysis, RNA-seq, CRISPR-Cas9 Kdm5c knockout mice, ChIP for H3K4me3, xenograft models Theranostics High 34522206
2022 KDM5C activates Xist lncRNA expression, required for stable X-inactivation, by converting H3K4me2/3 to H3K4me1 at the Xist locus. The Y-linked homolog KDM5D does not substitute for this function. This activity is conserved across eutherian and metatherian (marsupial) mammals and predates divergence of these lineages. Kdm5c conditional knockout in female cells (Xist RNA FISH), ectopic expression of mouse/human/marsupial/platypus KDM5C and KDM5D in male mESCs (Xist induction assay), H3K4 methylation ChIP Nature communications High 35545632
2022 TRIM11 is an E3 ubiquitin ligase for KDM5C that catalyzes K48-linked ubiquitin chains on KDM5C and promotes its proteasomal degradation. TRIM11 deficiency stabilizes KDM5C, and TRIM11/KDM5C regulate enhancer H3K4me3 at the MCAM gene to control cell migration. Co-immunoprecipitation (TRIM11–KDM5C), ubiquitination assay (K48-linked chain specificity), ChIP for H3K4me3 at MCAM enhancer, TRIM11 KO animal model Cell death & disease High 36192394
2022 The ARID domain of KDM5C is required for efficient nucleosome demethylation, whereas the PHD1 domain has an inhibitory role in KDM5C catalysis. 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 specificity, resulting in lower demethylase activity in the presence of flanking DNA. In vitro binding assays with nucleosomes, kinetic demethylase assays, domain deletion/mutagenesis, XLID patient mutation analysis Journal of molecular biology High 36495919
2022 KDM5C interacts with E2F6, which recruits KDM5C to the SF3A3 promoter where KDM5C demethylates H3K4me2 at the GpC island, leading to increased SF3A3 expression and bladder cancer progression. Co-immunoprecipitation (E2F6–KDM5C), ChIP for KDM5C and H3K4me2 at SF3A3 promoter, luciferase reporter assay Cancer cell international Medium 35248043
2024 KDM5C directly controls WNT signaling output during a specific developmental window to regulate the timely transition of primary to intermediate neural progenitor cells and neurogenesis. WNT inhibition during this window rescues transcriptomic and chromatin landscape changes in patient iPSC-derived cells and behavioral changes in Kdm5c-KO mice. A single WNT3A injection into wild-type embryonic mouse brains phenocopies KDM5C-related anxiety and memory alterations. Human patient iPSC differentiation, Kdm5c KO mouse behavioral studies, RNA-seq, ATAC-seq, WNT modulator treatment with rescue experiments, in vivo WNT3A injection Nature High 38383780
2024 KDM5C interacts with BRD4 via the BRD4 C-terminus, stimulates BRD4 enhancer recruitment, and BRD4 reciprocally stimulates the H3K4 demethylase activity of KDM5C. The cooperative action of KDM5C-associated BRD4 and H3K4me1/3 drives transcriptional activation of oncogenes. Pharmacological degradation of KDM5C reduces BRD4 chromatin enrichment and increases BET inhibitor efficacy. Co-immunoprecipitation (KDM5C–BRD4), ChIP-seq, RNA-seq, in vitro demethylase activity assay with BRD4, KDM5C KD/pharmacological degradation plus BETi combination in cell lines, organoids, and xenograft models Cancer research High 38285760
2024 KDM5C regulates dendritic cell (DC) heterogeneity and function: KDM5C-deficient DCs show increased proportions of cDC2Bs and cDC1s (partly type-I-IFN and pDC dependent) and an increase in Ly6C− pDCs. Loss of KDM5C increases expression of inflammatory genes, alters lineage-specific gene expression, and impairs CD8 T cell responses to Listeria infection through decreased antigen presentation by cDC1s. DC-specific Kdm5c conditional KO mice, flow cytometry, RNA-seq, Listeria infection model with CD8 T cell response readout Cell reports High 39052479
2024 KDM5C promotes global YY1 chromatin recruitment at promoters in a manner requiring an intact JmjC domain but independent of KDM5C histone demethylase activity. YY1 and KDM5C display a synthetic lethal interaction: dual depletion causes synergistic transcriptional repression of cell cycle and apoptosis genes and enhanced antitumor effect. Protein–protein interaction screen (pulldown), Co-immunoprecipitation (KDM5C–YY1), ChIP-seq for YY1 with KDM5C KD, RNA-seq, JmjC catalytic mutant analysis, siRNA double-KD viability assay EMBO reports High 39433896
2025 In male bone marrow mesenchymal stromal cells (LepR-MSCs), lower Kdm5c expression leads to increased Cxcl12 expression, providing superior hematopoietic support. MSC-specific Kdm5c KO in female mice increases MSC quantity/function and hematopoietic engraftment to male levels, establishing a Kdm5c–Cxcl12 axis that drives sex differences in the bone marrow niche. MSC-specific Kdm5c conditional KO, single-cell RNA-seq, in vitro colony formation co-culture, in vivo BM transplantation, Cxcl12 expression analysis The Journal of clinical investigation High 39836478
2016 Patient KDM5C mutations (Y751C, H514A, F642L but not D87G or A388P) suppress retinoic-acid-induced neurite growth in Neuro2a cells. The mutations prevent upregulation of neurite guidance genes including Ntng2, and reduced H3K4me3 at the Ntng2 promoter is observed. Ntng2 knockdown phenocopies KDM5C mutation-induced short neurites, and Ntng2 overexpression rescues the phenotype. Overexpression of patient-mutant KDM5C in Neuro2a cells, RNA-seq, ChIP for H3K4me3, Ntng2 siRNA knockdown and overexpression rescue, neurite length measurement Journal of molecular neuroscience Medium 27421841
2023 KDM5C acts as a transcriptional repressor in AML through its demethylase activity at promoters of bivalently marked immature genes. KDM5C knockdown results in globally increased H3K4me3 levels and upregulation of bivalently marked immature genes, causing a de-differentiation phenotype that can be reversed by modulating downstream mediators. In vivo shRNA screen in Cebpa-mutant AML mouse model, human/murine AML cell line proliferation assays, ChIP-seq for H3K4me3, RNA-seq, de-differentiation phenotype rescue Leukemia High 36631623
2025 KDM5C and KDM5D regulate overlapping but also distinct gene sets. KDM5C and KDM5D bind some overlapping genomic sites, but gene expression changes upon mutation are not directly caused by binding at affected gene promoters or enhancers, suggesting indirect mechanisms. Co-mutation of KDM5C rescues the tumor-suppressive phenotype of KDM5D mutation in male 786-O cells (xenograft model), consistent with co-occurrence of KDM5C mutation and Y chromosome loss in ccRCC. CRISPR-mediated mutation of KDM5C/KDM5D in ccRCC cell lines, RNA-seq, ChIP-seq, xenograft tumor formation assay Communications biology Medium 39955388
2007 NMR resonance assignment of the BRIGHT/ARID DNA-binding domain from human KDM5C/JARID1C was completed, providing backbone and sidechain 1H, 13C, and 15N assignments as a foundation for structural studies of this domain. NMR spectroscopy (1H, 13C, 15N resonance assignment of isolated ARID domain) Biomolecular NMR assignments Low 19636912
2024 Decreased JARID1C/KDM5C in diabetic plasmacytoid dendritic cells (pDCs) leads to increased IL-6 transcription, regulated upstream by an IFN-I/TYK2/JAK1,3 signaling pathway. KDM5C inhibition in non-diabetic pDCs skews naive CD4+ T cells toward a Th17 phenotype and increases IL-17A production. Human tissue and murine wound healing models, siRNA/inhibitor-based KDM5C loss-of-function in pDCs, IL-6 transcription assay, T cell co-culture Th17 skewing assay, pathway inhibitor experiments JCI insight Medium 38912581
2022 KDM5C promotes female-specific alcohol-associated liver fibrosis by downregulating the aryl hydrocarbon receptor (AhR) pathway in hepatic stellate cells. Kdm5b/Kdm5c double knockdown in female (but not male) mice prevents fibrosis and upregulates Ahr, Arnt, and Aip; re-knockdown of Ahr restores profibrotic gene expression. AAV-shRNA knockdown of Kdm5c (and Kdm5b) in male and female mice, RNA-seq, H3K4me3 ChIP-seq, liver fibrosis histology, AhR epistasis experiment Hepatology communications Medium 35468265
2025 KDM5C physically interacts with CRBN (cereblon) and stabilizes CRBN protein in an enzyme-activity-independent manner, thereby enhancing sensitivity of AML cells to lenalidomide. MLN4924 increases CRBN by elevating KDM5C levels. TurboID proximity labeling plus quantitative proteomics (interactome), co-immunoprecipitation (KDM5C–CRBN), KDM5C overexpression/KD with lenalidomide viability assay, KDM5C inhibitor treatment Cellular & molecular biology letters Medium 39881283

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 553 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 313 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 192 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 111 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 92 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 91 34522206
2020 X chromosome dosage of histone demethylase KDM5C determines sex differences in adiposity. The Journal of clinical investigation 87 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 64 29339538
2015 Mutations in the intellectual disability gene KDM5C reduce protein stability and demethylase activity. Human molecular genetics 62 25666439
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
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 54 29670509
2015 H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing. Nucleic acids research 53 25712104
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) 52 33977073
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
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
2020 Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation. Communications biology 44 32483278
2015 Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders. European journal of human genetics : EJHG 44 26059843
2020 LncRNA LOXL1-AS1 is transcriptionally activated by JUND and contributes to osteoarthritis progression via targeting the miR-423-5p/KDM5C axis. Life sciences 39 32679142
2019 KDM5C is transcriptionally regulated by BRD4 and promotes castration-resistance prostate cancer cell proliferation by repressing PTEN. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 38 30921702
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
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
2018 KDM5c inhibits multidrug resistance of colon cancer cell line by down-regulating ABCC1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 33 30257334
2016 Enhancement of Proliferation and Invasion of Gastric Cancer Cell by KDM5C Via Decrease in p53 Expression. Technology in cancer research & treatment 33 26858085
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 27 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
2023 The histone demethylase KDM5C functions as a tumor suppressor in AML by repression of bivalently marked immature genes. Leukemia 21 36631623
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
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 20 32081420
2015 Mutations in the KDM5C ARID Domain and Their Plausible Association with Syndromic Claes-Jensen-Type Disease. International journal of molecular sciences 20 26580603
2020 E6 hijacks KDM5C/lnc_000231/miR-497-5p/CCNE1 axis to promote cervical cancer progression. Journal of cellular and molecular medicine 19 32818316
2016 XCI-escaping gene KDM5C contributes to ovarian development via downregulating miR-320a. Human genetics 18 27896428
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
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
2024 Histone demethylase JARID1C/KDM5C regulates Th17 cells by increasing IL-6 expression in diabetic plasmacytoid dendritic cells. JCI insight 12 38912581
2023 Exploration of Morphological Features of Clear Cell Renal Cell Carcinoma With PBRM1, SETD2, BAP1, or KDM5C Mutations. International journal of surgical pathology 12 36911986
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
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
2025 Sexual dimorphism in the mouse bone marrow niche regulates hematopoietic engraftment via sex-specific Kdm5c/Cxcl12 signaling. The Journal of clinical investigation 7 39836478
2023 PBRM1 and KDM5C cooperate to define high-angiogenesis tumors and increased antiangiogenic response in renal cancer. American journal of cancer research 6 37293154
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
2024 KDM5C-Mediated Recruitment of BRD4 to Chromatin Regulates Enhancer Activation and BET Inhibitor Sensitivity. Cancer research 5 38285760
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
2025 The histone demethylase KDM5C enhances the sensitivity of acute myeloid leukemia cells to lenalidomide by stabilizing cereblon. Cellular & molecular biology letters 4 39881283
2025 KDM5C and KDM5D mutations have different consequences in clear cell renal cell carcinoma cells. Communications biology 4 39955388
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
2024 Targeting the transcription factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C. EMBO reports 3 39433896

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