Affinage

KDM5A

Lysine-specific demethylase 5A · UniProt P29375

Length
1690 aa
Mass
192.1 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDM5A is a JmjC-domain histone demethylase that removes mono-, di-, and trimethylation from H3K4, functioning as a transcriptional repressor at developmentally regulated, cell-cycle, and metabolic genes through its association with chromatin-remodeling complexes including NuRD, SIN3B-HDAC, and the Notch/RBP-J repressor (PMID:25190814, PMID:20231316, PMID:23093672). Its catalytic activity is allosterically stimulated by a positive-feedback mechanism in which the PHD1 domain binds the unmethylated H3K4 product, and is further modulated by SMYD2-mediated methylation at K1063, while an intrinsically disordered region engages the nucleosome acidic patch and DNA for efficient substrate demethylation (PMID:25686748, PMID:41962864, PMID:40545232). Beyond canonical repression, KDM5A exhibits demethylase-independent functions, including inhibition of HDAC1 activity within the CLOCK-BMAL1 complex to regulate circadian transcription, and it is recruited to DNA double-strand breaks via PAR-binding and macroH2A1.2 to promote ZMYND8-NuRD-dependent transcriptional silencing and homologous recombination repair (PMID:21960634, PMID:28572115, PMID:34003252). Loss-of-function mutations in KDM5A cause autism spectrum disorder with speech deficits, as demonstrated by human genetics and Kdm5a knockout mice exhibiting repetitive behaviors, sociability deficits, and abnormal dendritic morphogenesis (PMID:33350388).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 Medium

    KDM5A was first linked to human disease through identification of the NUP98-JARID1A fusion in pediatric AML, establishing that its chromatin-regulatory domains could be co-opted in oncogenic fusions.

    Evidence 3' RACE, RT-PCR, FISH, and karyotyping in a pediatric AML case with t(11;21)

    PMID:16419055

    Open questions at the time
    • Fusion protein mechanism not characterized
    • No functional assays for the fusion oncoprotein performed
  2. 2010 High

    Two studies established KDM5A as an oxygen-dependent H3K4me3 demethylase whose enzymatic activity is integrated into the Notch/RBP-J transcriptional repressor complex, demonstrating that KDM5A links signal-responsive transcription factor complexes to histone demethylation.

    Evidence In vitro demethylase assays under hypoxia, Co-IP/ChIP of KDM5A-RBP-J, Drosophila conservation analysis

    PMID:20231316 PMID:20406991

    Open questions at the time
    • Structural basis for KDM5A-RBP-J interaction unknown
    • How oxygen sensing integrates with signaling-dependent recruitment not resolved
  3. 2011 High

    Discovery that KDM5A functions within the CLOCK-BMAL1 complex to regulate circadian gene expression independently of its demethylase activity — by inhibiting HDAC1 — revealed an unexpected catalysis-independent chromatin regulatory role.

    Evidence Co-IP, ChIP at Per2 promoter, siRNA knockdown in mammalian cells, Drosophila genetic validation

    PMID:21960634

    Open questions at the time
    • Mechanism by which KDM5A inhibits HDAC1 activity not defined at molecular level
    • Whether demethylase-independent function extends to other loci unclear
  4. 2012 High

    Multiple studies converged to show that KDM5A operates as a corepressor in diverse developmental and cell-cycle contexts — silencing RB-target genes during senescence, E2F4-target cell-cycle genes during differentiation, and embryonic globin genes in concert with G9a — establishing it as a broadly used transcriptional silencer.

    Evidence ChIP-seq in ES cells and primary human cells, KO/KD with transcriptomic phenotypes, Co-IP of KDM5A-G9a complex

    PMID:22615382 PMID:23093672 PMID:23112189

    Open questions at the time
    • Whether KDM5A directly contacts RB or E2F4 proteins not demonstrated
    • How KDM5A is selectively recruited to different gene sets not resolved
  5. 2014 High

    Biochemical purification established that KDM5A is a stable subunit of both SIN3B-HDAC and NuRD complexes and co-regulates hundreds of developmental genes with NuRD, with genetic epistasis in C. elegans confirming functional conservation of this partnership.

    Evidence Immunoaffinity purification, sucrose gradient, sequential IP, ChIP, C. elegans epistasis

    PMID:25190814

    Open questions at the time
    • Which KDM5A domain mediates NuRD versus SIN3B interaction not mapped
    • Whether KDM5A exists simultaneously in both complexes or is partitioned unclear
  6. 2015 High

    The positive-feedback allosteric mechanism was uncovered: PHD1 binds unmethylated H3K4 (the demethylation product) and stimulates JmjC catalytic activity, explaining how KDM5A can spread demethylation across nucleosomes; separately, KDM5A was linked to mitochondrial metabolism through repression of PGC-1α target genes.

    Evidence NMR structure of PHD1, in vitro demethylation on nucleosomes with mutagenesis; Kdm5a KO mouse with metabolic and RNA-seq phenotyping

    PMID:25686748 PMID:26314709

    Open questions at the time
    • Full-length structural context of PHD1-catalytic domain communication not determined
    • Whether allosteric mechanism operates equivalently on all methylation states unknown
  7. 2017 High

    KDM5A was shown to demethylate H3K4me3 at DNA double-strand breaks, a prerequisite for ZMYND8-NuRD binding, transcriptional silencing at damage sites, and homologous recombination, thus revealing a direct role in the DNA damage response.

    Evidence ChIP at defined DSBs, HR reporter assay, siRNA knockdown

    PMID:28572115

    Open questions at the time
    • How KDM5A is initially recruited to DSBs not determined in this study
    • Whether catalytic activity versus scaffolding is sufficient for repair not separated
  8. 2018 High

    X-ray crystallography of the KDM5A catalytic domain revealed a druggable active site with a unique noncatalytic cysteine (Cys481) amenable to covalent inhibition, providing the first high-resolution structural view of the enzyme.

    Evidence Co-crystal structures with inhibitors N70/N71, enzyme kinetics, dialysis/reversibility assays

    PMID:30392349

    Open questions at the time
    • No full-length structure available
    • How PHD1-catalytic domain coupling occurs structurally remains unresolved
  9. 2020 High

    Detailed biochemical characterization of substrate recognition showed that KDM5A requires H3Q5 and a distal H3 epitope (residues 14–18) for efficient catalysis, and NMR structures of apo versus H3-bound PHD1 revealed conformational changes, deepening the mechanistic understanding of allosteric regulation.

    Evidence Systematic alanine scanning, quantitative demethylase assays, NMR solution structures, fluorescence polarization

    PMID:31985200 PMID:33621062

    Open questions at the time
    • How chromatin modifications at the distal epitope integrate with allosteric activation in vivo unknown
    • No cryo-EM or full-length structure capturing PHD1-JmjC communication
  10. 2020 High

    Human genetic and mouse knockout studies demonstrated that KDM5A mutations cause autism spectrum disorder, linking the demethylase to neurodevelopmental function through regulation of dendritic morphogenesis and hippocampal gene expression.

    Evidence Forward genetics, WES in human ASD families, Kdm5a KO mouse behavioral/cellular/transcriptomic phenotyping

    PMID:33350388

    Open questions at the time
    • Specific neuronal target genes mediating behavioral phenotype not fully defined
    • Whether catalytic activity or scaffolding roles drive the ASD phenotype not separated
  11. 2021 High

    The recruitment mechanism of KDM5A to DNA damage sites was resolved: a noncanonical PAR-binding coiled-coil region unique to KDM5A mediates PARP-dependent recruitment, and the histone variant macroH2A1.2 acts upstream, connecting KDM5A's DSB function to PARylation signaling.

    Evidence Domain mutagenesis, PAR-binding assays, PARP inhibitor treatment, macroH2A1.2 KD, HR reporter

    PMID:34003252

    Open questions at the time
    • Whether PAR binding and macroH2A1.2 act in the same linear pathway or parallel pathways not fully resolved
    • Structural basis of the PAR-binding coiled-coil not determined
  12. 2025 High

    An intrinsically disordered region in KDM5A was found to engage the nucleosome acidic patch and DNA through bifunctional arginine-rich motifs, revealing a previously unrecognized mechanism for nucleosome-level substrate recognition essential for catalytic activity.

    Evidence Cross-linking mass spectrometry, mutagenesis, in vitro demethylation on nucleosome substrates

    PMID:40545232

    Open questions at the time
    • How IDR-nucleosome contacts integrate with PHD1 allosteric activation not determined
    • In vivo relevance of IDR-nucleosome interaction not tested
  13. 2026 High

    SMYD2-mediated methylation of KDM5A at K1063 was identified as a post-translational regulatory mechanism that attenuates demethylase activity and reshapes the KDM5A interactome, establishing a new layer of regulation beyond substrate-level allostery.

    Evidence In vitro methylation assay, K1063 mutagenesis, genome-wide ChIP-seq, interactome MS, proliferation assays

    PMID:41962864

    Open questions at the time
    • Whether K1063 methylation is dynamically regulated in physiological contexts unknown
    • The specific interactors gained or lost upon methylation not fully characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length structural model integrating PHD1 allostery, the IDR-nucleosome interface, and catalytic domain communication is still lacking, and the rules governing how KDM5A switches between demethylase-dependent repression and demethylase-independent activation remain undefined.
  • No cryo-EM or full-length structure of KDM5A on a nucleosome substrate
  • Molecular basis of demethylase-independent transcriptional activation not resolved
  • How KDM5A is partitioned among distinct chromatin complexes in a cell-type-specific manner is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0140110 transcription regulator activity 4 GO:0042393 histone binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005634 nucleus 6 GO:0005694 chromosome 4
Pathway
R-HSA-4839726 Chromatin organization 9 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 2 R-HSA-9909396 Circadian clock 1
Partners
CHD4G9AGATA1HDAC1RBPJSMYD2WDR5ZMYND8
Complex memberships
CLOCK-BMAL1NuRDRBP-J/Notch repressorSIN3B-HDAC

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 KDM5A is an integral component of the Notch/RBP-J repressor complex; KDM5A physically interacts with RBP-J and dynamically erases H3K4 methylation at RBP-J target sites upon Notch signaling inhibition, with this interaction conserved in Drosophila and required for Notch-induced growth responses. Co-immunoprecipitation, ChIP, genetic conservation analysis (Drosophila), loss-of-function studies Genes & development High 20231316
2011 KDM5A (JARID1a) forms a complex with CLOCK-BMAL1 and is recruited to the Per2 promoter; it enhances CLOCK-BMAL1 transcription by inhibiting HDAC1 function in a demethylase-independent manner, and its depletion dampens circadian gene expression and shortens circadian period. Co-immunoprecipitation, ChIP, siRNA knockdown, Drosophila genetic loss-of-function Science High 21960634
2010 KDM5A (JARID1A) is the major H3K4 demethylase in bronchial epithelial cells; hypoxia inhibits KDM5A enzymatic activity (requiring molecular oxygen as cofactor) without altering its mRNA or protein levels, leading to global and gene-specific increases in H3K4me3. In vitro histone demethylation assay with nuclear extracts, siRNA knockdown, ChIP Cancer research High 20406991
2012 KDM5A (Jarid1a) cooperates with the retinoblastoma tumor suppressor to silence H3K4-methylated target genes during cellular senescence; Jarid1a/b-mediated H3K4 demethylation contributes to retinoblastoma-dependent gene silencing. Quantitative mass spectrometry, ChIP-seq, functional knockdown studies in primary human cells Proceedings of the National Academy of Sciences of the United States of America High 22615382
2012 KDM5A cooperates with E2F4 to repress cell cycle genes during differentiation; KDM5A co-occupies E2F4 target genes genome-wide and its knockout leads to derepression of these loci; in terminally differentiated cells, common targets are bound by p130/DREAM complex. ChIP-seq (global location analysis), KDM5A knockout in ES cells, co-occupancy analysis Proceedings of the National Academy of Sciences of the United States of America High 23093672
2012 KDM5A (Jarid1a) physically associates with the H3K9 methyltransferase G9a/KMT1C in a corepressor complex distinct from the G9a-Mediator coactivator complex; coordinate action of G9a and Jarid1a (concurrent H3K9me2 deposition and H3K4me3 removal) maintains silencing of the embryonic globin gene. Co-immunoprecipitation, ChIP, functional knockdown, reporter assays Proceedings of the National Academy of Sciences of the United States of America High 23112189
2014 KDM5A is physically and functionally associated with both the SIN3B-containing HDAC complex and the NuRD complex; KDM5A depletion co-regulates hundreds of developmentally regulated genes with NuRD catalytic subunit CHD4, and the C. elegans homologs function in the same genetic pathway during vulva development. Immunoaffinity purification, sucrose density gradient, sequential immunoprecipitation, ChIP, genetic epistasis in C. elegans The Journal of biological chemistry High 25190814
2015 KDM5A PHD1 domain preferentially binds unmethylated H3K4 (the product of KDM5A demethylation); binding of unmodified H3 to PHD1 allosterically stimulates the catalytic domain to demethylate H3K4me3 on peptide and nucleosome substrates, establishing a positive-feedback mechanism. Biochemical binding assays, NMR structural studies, in vitro demethylation assays on peptide and nucleosome substrates, mutagenesis Nature communications High 25686748
2015 Loss of Kdm5a restores differentiation in pRb-deficient cells by increasing mitochondrial respiration; KDM5A is a direct repressor of metabolic regulatory genes and its deletion activates Pgc-1α target genes, linking H3K4 demethylation to mitochondrial biogenesis and differentiation. KO mouse model, RNA-seq, ChIP, metabolic (oxygen consumption) assays, gain-of-function rescue Genes & development High 26314709
2016 KDM5A associates with the NF-κB subunit p50 and binds to the Socs1 promoter in resting NK cells, decreasing H3K4me3 and maintaining a repressive chromatin configuration at Socs1; loss of Kdm5a increases Socs1 expression, impairs STAT4 phosphorylation and nuclear localization, and reduces NK cell IFN-γ production. Co-immunoprecipitation, ChIP, Kdm5a knockout mice, NK cell activation assays Cell reports High 27050510
2017 KDM5A demethylates H3K4me3 near DNA double-strand break (DSB) sites; this demethylation is required for ZMYND8-NuRD complex binding to damaged chromatin, transcriptional silencing at DSBs, and homologous recombination repair. ChIP near DSBs, siRNA knockdown, DSB repair assays (HR reporter), transcriptional silencing assays at defined DSBs The Journal of cell biology High 28572115
2018 KDM5A catalytic domain structure was determined by X-ray crystallography in complex with inhibitors N70 and N71; a noncatalytic cysteine (Cys481) unique to KDM5 family near the active site allows covalent modification by acrylamide-containing inhibitors that inhibit in an αKG-competitive but irreversible manner. X-ray crystallography (co-crystal structures), enzyme inhibition assays, dialysis/reversibility assays Journal of medicinal chemistry High 30392349
2019 KDM5A sustains ASCL1 expression and neuroendocrine differentiation in SCLC by repressing NOTCH2 and Notch target genes; CRISPR KO of KDM5A in a mouse SCLC model decreased tumorigenesis and metastasis while increasing Notch signaling. CRISPR/Cas9 KO (in vitro and in vivo mouse model), gene expression analysis, ChIP Genes & development High 31727771
2021 KDM5A contains a noncanonical poly(ADP-ribose) (PAR)-binding coiled-coil region unique among KDM5 family members; loss of this PAR-binding region or PARP inhibitor treatment blocks KDM5A-PAR interactions and its DNA repair functions. The histone variant macroH2A1.2 is also specifically required upstream of KDM5A for its recruitment to DNA damage sites and homology-directed repair. Domain mutagenesis, PAR-binding assays, PARP inhibitor treatment, macroH2A1.2 KD, HR reporter assays, ChIP at DSBs The Journal of cell biology High 34003252
2020 The KDM5A PHD1 domain binds the H3 tail with preference for lower methylation states of H3K4 (me0 > me1 > me2 > me3); NMR solution structures of apo and H3-bound PHD1 show conformational changes accommodating H3 in a helical conformation, and post-translational modifications at the distal H3 epitope (residues 14–18) modulate KDM5A demethylation activity. NMR spectroscopy (solution structure), fluorescence polarization binding assays, demethylation activity assays, mutagenesis ACS chemical biology High 33621062
2020 KDM5A extended substrate recognition of H3 tail involves H3Q5 as critical for demethylation and a distal epitope at positions 14–18 whose deletion increases KMapp ~8-fold; post-translational modifications on the distal epitope modulate KDM5A-dependent demethylation. Alanine scanning mutagenesis, in vitro demethylation activity assays Biochemistry High 31985200
2019 KDM5A acts as a transcriptional repressor of MPC-1 by binding directly to its promoter and demethylating H3K4, suppressing mitochondrial pyruvate metabolism in pancreatic cancer cells; KDM5A expression is inversely correlated with MPC-1 in patient samples. ChIP assay, overexpression and knockdown experiments, in vitro and in vivo tumor growth assays Oncogene Medium 31641207
2019 KDM5A promotes preadipocyte differentiation by repressing Wnt6 transcription; C/EBPβ binds the KDM5A promoter to transactivate its expression, and KDM5A interacts with C/EBPβ and cooperates with it to reduce H3K4me3 at the Wnt6 promoter, inhibiting Wnt/β-catenin signaling. ChIP, immunoprecipitation, RT-qPCR, siRNA knockdown in 3T3-L1 cells The Journal of biological chemistry Medium 31061100
2022 Fbxo22 reduces KDM5A protein levels via ubiquitination; KDM5A promotes H3K4me3 demethylation at the p16 promoter to downregulate p16 expression, and Fbxo22-mediated KDM5A degradation rescues p16 expression to suppress TNBC tumorigenesis. Immunoprecipitation/ubiquitination assay, ChIP, knockdown/overexpression, in vitro and in vivo tumor assays Cell biology and toxicology Medium 36112263
2023 KDM5A physically interacts with MLL1, MLL2, and WDR5 (normally its functional antagonists); when bound at mesenchymal gene promoters KDM5A acts as a transcriptional activator by inhibiting HDAC activity and increasing H3K18ac, while at E-cadherin promoter it acts as a classical repressor by demethylating H3K4me3. ChIP, co-immunoprecipitation, HDAC activity assays, gene expression analysis Biochimica et biophysica acta. Gene regulatory mechanisms Medium 37722486
2019 HDAC1 negatively regulates RBPJ occupancy on mitotic chromatin in a KDM5A-dependent manner; KDM5A knockdown or inactivation reduces HDAC1-dependent regulation of RBPJ mitotic chromatin binding, and KDM5A presence at these sites is essential for increased RBPJ occupancy. ChIP on mitotic chromatin, siRNA knockdown, HDAC1 inhibitor treatment Nucleic acids research Medium 30916347
2020 KDM5A mutations cause autism spectrum disorder (ASD) with lack of speech; Kdm5a knockout mice display repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis, with dysregulation of the hippocampal transcriptome. Forward genetics screen, Kdm5a knockout mouse model, behavioral assays, RNA-seq, dendritic morphology analysis, human WES/microarray eLife High 33350388
2016 KDM5A controls BMP2-induced osteogenic differentiation of bone marrow mesenchymal stem cells by decreasing H3K4me3 levels at the Runx2 promoter in a demethylase activity-dependent manner; elevated KDM5A in osteoporotic MSCs impairs BMP2-induced osteogenesis. ChIP, shRNA knockdown, KDM5A inhibitor, overexpression, OVX mouse model Cell death & disease Medium 27512956
2006 KDM5A (JARID1A) is identified as a fusion partner of NUP98 in pediatric AML through the t(11;21) translocation, generating a NUP98-JARID1A fusion oncoprotein implicated in transcriptional regulation. 3' RACE, RT-PCR, FISH, karyotyping Genes, chromosomes & cancer Medium 16419055
2023 RepID recruits CRL4A-JARID1A (KDM5A) to the DAB2 promoter during proliferation, maintaining H3K4 demethylation and repressive chromatin; during megakaryocytic differentiation, RepID, CRL4A, and JARID1A dissociate from chromatin, allowing euchromatinization and DAB2 expression. Immunoprecipitation, proximity ligation assay, ChIP-qPCR, subcellular fractionation Cell communication and signaling Medium 37612584
2020 KDM5A acts as an H3K4me3 demethylase at the miR-495 promoter in prostate cancer cells, inhibiting miR-495 transcription; reduced miR-495 elevates YTHDF2, which degrades MOB3B mRNA via m6A recognition, promoting cancer progression. ChIP assay, dual luciferase reporter, PAR-CLIP, me-RIP, xenograft mouse model Journal of experimental & clinical cancer research Medium 33087165
2020 KDM5A in neural progenitors binds to and activates neuronal genes involved in early differentiation; mitochondrial damage causes characteristic KDM5A protein degradation in neural progenitors, inhibiting neuronal differentiation and adult hippocampal neurogenesis. Proteomics, KDM5A overexpression/knockdown in neural progenitors, neurogenesis assays, KO mouse Experimental & molecular medicine Medium 36056186
2011 KDM5A (JARID1A) binds in a ligand-independent manner to a progesterone receptor gene upstream regulatory region and represses progesterone receptor promoter activity through its demethylase activity; JARID1A depletion elevates H3K4me3 in this region and increases progesterone receptor expression. ChIP, overexpression of wild-type vs. catalytically inactive JARID1A mutant, siRNA knockdown, reporter assay The FEBS journal Medium 21348942
2025 KDM5A contains an intrinsically disordered region (IDR) with bifunctional arginine-rich motifs that bind both the histone H2A/H2B acidic patch and nucleosomal DNA; these multivalent interactions with the nucleosome are necessary for KDM5A catalytic activity on nucleosome substrates. Cross-linking mass spectrometry, binding assays, mutagenesis, in vitro demethylation assays on nucleosomes Journal of molecular biology High 40545232
2026 KDM5A is methylated by SMYD2 at K1063; this methylation decreases KDM5A histone demethylase activity and alters its protein interactome; a K1063 mutant unable to be methylated demethylates H3K4me3 more robustly at additional genomic loci and affects cell proliferation pathways. In vitro methylation assay, site-directed mutagenesis, genome-wide ChIP-seq, protein interactome (MS), cell growth assays The Journal of biological chemistry High 41962864
2020 The direct physical contact between GATA1 and the second PHD domain of KDM5A (JARID1A) was identified in erythroid cells, along with an interaction with SCL, linking KDM5A to the haematopoietic transcription factor machinery. Co-immunoprecipitation, pull-down assays with defined PHD domain constructs Royal Society open science Medium 32218938
2024 KDM5A suppresses HIV-1 Tat/LTR-mediated viral transcription in latent cells by maintaining H3K4me3 demethylation at the HIV-1 5' LTR promoter; deletion or inhibition of KDM5A reactivates HIV-1 lytic replication in latently infected T cells and microglia. KDM5A KO/inhibitor (JQKD82), ChIP for H3K4me3 at HIV-1 LTR, latency reactivation assays, PBMCs from HIV-1 patients Antiviral research Medium 38925368
2024 KDM5A deficiency in endothelial cells exacerbates aging; mechanistically, loss of KDM5A increases H3K4me3 enrichment at the FABP4 promoter, driving active FABP4 transcription and fatty acid metabolism disorders; endothelial-specific KDM5A-deficient mice show shortened lifespan and multiple senescent phenotypes. Endothelial-specific KO mouse model, ChIP for H3K4me3 at FABP4 promoter, metabolic assays, lifespan analysis Advanced science Medium 41236095
2024 KDM5A suppresses expression of the antigen-presentation pathway genes (e.g., HLA-A, HLA-B) in epithelial ovarian cancer; KDM5A inhibition restores antigen-presentation gene expression and promotes CD8+ T cell-mediated antitumor immunity in syngeneic mouse models. KDM5A knockdown, gene expression analysis, in vivo syngeneic tumor model with CD8+ T cell assessment Cancer immunology research Medium 35726891
2024 KDM5A and KDM5B suppress transcription of endogenous retroviral elements (ERVs) via maintenance of KRAB-ZNF gene expression; loss of KDM5A (by gene inactivation or acute dTAG degradation) elevates ERV expression, increases dsRNA levels, and activates immune response genes. This regulation requires KDM5A protein rather than its demethylase activity, and KDM5A co-immunoprecipitates with the NuRD complex. KO and dTAG acute degradation, RNA-seq, ATAC-seq, H3K4me3 ChIP-seq, pan-KDM5 inhibitor treatment, Co-immunoprecipitation of KDM5A-NuRD bioRxiv (preprint)preprint Medium 39386707
2025 KDM5A maintains H3K4 hypomethylation at the Il4 promoter in CD4+ T cells, facilitating STAT6/GATA3 recruitment for IL-4 transcription; TCR signaling stabilizes KDM5A via USP7-mediated deubiquitination, and KDM5A deficiency abolishes TCR-induced IL-4 production. CD4+ T cell-specific Kdm5a KO mice, ChIP-qPCR at Il4 promoter, ubiquitination assays, USP7 knockdown Immunology Medium 41188062

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science (New York, N.Y.) 181 21960634
2010 Histone demethylase KDM5A is an integral part of the core Notch-RBP-J repressor complex. Genes & development 150 20231316
2017 Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair. The Journal of cell biology 137 28572115
2012 H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. Proceedings of the National Academy of Sciences of the United States of America 126 22615382
2018 Selective Inhibition of Lysine-Specific Demethylase 5A (KDM5A) Using a Rhodium(III) Complex for Triple-Negative Breast Cancer Therapy. Angewandte Chemie (International ed. in English) 122 29968419
2015 The histone demethylase KDM5A is a key factor for the resistance to temozolomide in glioblastoma. Cell cycle (Georgetown, Tex.) 107 26566863
2012 Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer. American journal of translational research 107 22937203
2010 Hypoxia induces trimethylated H3 lysine 4 by inhibition of JARID1A demethylase. Cancer research 101 20406991
2015 Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism. Nature communications 100 25686748
2019 The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis. Genes & development 99 31727771
2006 Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. Genes, chromosomes & cancer 99 16419055
2016 KDM5A controls bone morphogenic protein 2-induced osteogenic differentiation of bone mesenchymal stem cells during osteoporosis. Cell death & disease 87 27512956
2020 Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression. Journal of experimental & clinical cancer research : CR 83 33087165
2012 Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A. Proceedings of the National Academy of Sciences of the United States of America 74 23112189
2012 Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation. Proceedings of the National Academy of Sciences of the United States of America 71 23093672
2015 Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells. Genes & development 66 26314709
2014 Physical and functional interactions between the histone H3K4 demethylase KDM5A and the nucleosome remodeling and deacetylase (NuRD) complex. The Journal of biological chemistry 65 25190814
2016 H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1. Cell reports 63 27050510
2019 Structure-Based Discovery of a Selective KDM5A Inhibitor that Exhibits Anti-Cancer Activity via Inducing Cell Cycle Arrest and Senescence in Breast Cancer Cell Lines. Cancers 60 30650517
2019 A novel KDM5A/MPC-1 signaling pathway promotes pancreatic cancer progression via redirecting mitochondrial pyruvate metabolism. Oncogene 49 31641207
2020 Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade. Science translational medicine 44 32908002
2021 Hypoxia promotes the metastasis of pancreatic cancer through regulating NOX4/KDM5A-mediated histone methylation modification changes in a HIF1A-independent manner. Clinical epigenetics 42 33499904
2019 Histone demethylase KDM5A is transactivated by the transcription factor C/EBPβ and promotes preadipocyte differentiation by inhibiting Wnt/β-catenin signaling. The Journal of biological chemistry 42 31061100
2021 ELK4 promotes the development of gastric cancer by inducing M2 polarization of macrophages through regulation of the KDM5A-PJA2-KSR1 axis. Journal of translational medicine 41 34372882
2017 KDM5A promotes proliferation and EMT in ovarian cancer and closely correlates with PTX resistance. Molecular medicine reports 41 28714030
2020 KDM5A mutations identified in autism spectrum disorder using forward genetics. eLife 39 33350388
2021 Pharmacological inhibition of KDM5A for cancer treatment. European journal of medicinal chemistry 36 34555614
2018 The histone demethylase KDM5A is required for the repression of astrocytogenesis and regulated by the translational machinery in neural progenitor cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 36 29212818
2018 Genome-Wide Methylation Analysis Identifies NOX4 and KDM5A as Key Regulators in Inhibiting Breast Cancer Cell Proliferation by Ginsenoside Rg3. The American journal of Chinese medicine 35 30149757
2018 Targeting histone demethylases KDM5A and KDM5B in AML cancer cells: A comparative view. Leukemia research 34 29602065
2019 The therapeutic effect of dexmedetomidine on protection from renal failure via inhibiting KDM5A in lipopolysaccharide-induced sepsis of mice. Life sciences 31 31682847
2021 KDM5A silencing transcriptionally suppresses the FXYD3-PI3K/AKT axis to inhibit angiogenesis in hepatocellular cancer via miR-433 up-regulation. Journal of cellular and molecular medicine 29 33621431
2020 Effect of histone demethylase KDM5A on the odontogenic differentiation of human dental pulp cells. Bioengineered 29 32208897
2021 Poly(ADP-ribose) binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions. The Journal of cell biology 28 34003252
2018 Histone demethylase KDM5A inhibits glioma cells migration and invasion by down regulating ZEB1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 28 29324315
2020 Molecular mechanisms of KDM5A in cellular functions: Facets during development and disease. Experimental cell research 27 33010254
2019 Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities. Blood advances 27 31698461
2022 Inhibition of KDM5A attenuates cisplatin-induced hearing loss via regulation of the MAPK/AKT pathway. Cellular and molecular life sciences : CMLS 25 36396833
2018 Structure-Based Engineering of Irreversible Inhibitors against Histone Lysine Demethylase KDM5A. Journal of medicinal chemistry 25 30392349
2014 Increased progesterone receptor A expression in labouring human myometrium is associated with decreased promoter occupancy by the histone demethylase JARID1A. Molecular human reproduction 25 24442343
2012 Association of IGF1 and KDM5A polymorphisms with performance, fatness and carcass traits in chickens. Journal of applied genetics 25 23275255
2011 The histone demethylase JARID1A regulates progesterone receptor expression. The FEBS journal 25 21348942
2022 Drawing a line between histone demethylase KDM5A and KDM5B: their roles in development and tumorigenesis. Experimental & molecular medicine 24 36509829
2019 Identification of ryuvidine as a KDM5A inhibitor. Scientific reports 24 31289306
2020 Extended Recognition of the Histone H3 Tail by Histone Demethylase KDM5A. Biochemistry 21 31985200
2017 SNP co-association and network analyses identify E2F3, KDM5A and BACH2 as key regulators of the bovine milk fatty acid profile. Scientific reports 21 29230020
2022 Aβ-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation. Experimental & molecular medicine 19 36056186
2022 Fbxo22 inhibits metastasis in triple-negative breast cancer through ubiquitin modification of KDM5A and regulation of H3K4me3 demethylation. Cell biology and toxicology 19 36112263
2021 lncRNA NEAT1 facilitates the progression of colorectal cancer via the KDM5A/Cul4A and Wnt signaling pathway. International journal of oncology 19 34109988
2012 The EP300, KDM5A, KDM6A and KDM6B chromatin regulators cooperate with KLF4 in the transcriptional activation of POU5F1. PloS one 19 23272250
2021 Histone demethylase KDM5A promotes tumorigenesis of osteosarcoma tumor. Cell death discovery 17 33436536
2016 Vitamin C promotes pluripotency of human induced pluripotent stem cells via the histone demethylase JARID1A. Biological chemistry 17 27343473
2019 HDAC1 negatively regulates selective mitotic chromatin binding of the Notch effector RBPJ in a KDM5A-dependent manner. Nucleic acids research 15 30916347
2022 KDM5A Inhibits Antitumor Immune Responses Through Downregulation of the Antigen-Presentation Pathway in Ovarian Cancer. Cancer immunology research 14 35726891
2016 Depletion of Histone Demethylase Jarid1A Resulting in Histone Hyperacetylation and Radiation Sensitivity Does Not Affect DNA Double-Strand Break Repair. PloS one 13 27253695
2021 Recognition of Histone H3 Methylation States by the PHD1 Domain of Histone Demethylase KDM5A. ACS chemical biology 12 33621062
2020 Targeting of KDM5A by miR-421 in Human Ovarian Cancer Suppresses the Progression of Ovarian Cancer Cells. OncoTargets and therapy 12 33061428
2023 The pediatric leukemia oncoprotein NUP98-KDM5A induces genomic instability that may facilitate malignant transformation. Cell death & disease 11 37301844
2017 Repair of Calvarial Bone Defect Using Jarid1a-Knockdown Bone Mesenchymal Stem Cells in Rats. Tissue engineering. Part A 11 28903624
2023 Domain architecture and protein-protein interactions regulate KDM5A recruitment to the chromatin. Epigenetics 10 37838974
2022 KDM5A regulates the growth and gefitinib drug resistance against human lung adenocarcinoma cells. 3 Biotech 10 35371900
2023 LINC00092 derived from follicular fluid alleviated the symptoms of PCOS through inactivation of phosphatase and tensin homolog by recruiting KDM5A. Reproductive biology 9 37084543
2023 FOXP2 suppresses the proliferation, invasion, and aerobic glycolysis of hepatocellular carcinoma cells by regulating the KDM5A/FBP1 axis. Environmental toxicology 9 37713600
2020 KDM5A and PHF2 positively control expression of pro-metastatic genes repressed by EWS/Fli1, and promote growth and metastatic properties in Ewing sarcoma. Oncotarget 9 33196691
2017 KDM5A demethylase: Erasing histone modifications to promote repair of DNA breaks. The Journal of cell biology 9 28572116
2014 Distinctive changes in histone H3K4 modification mediated via Kdm5a expression in spermatogonial stem cells of cryptorchid testes. The Journal of urology 9 24679876
2023 Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity. Science advances 8 37992166
2021 Histone demethylase KDM5A enhances cell proliferation, induces EMT in lung adenocarcinoma cells, and have a strong causal association with paclitaxel resistance. Acta biochimica Polonica 8 34270886
2022 Histone demethylase KDM5A regulates the functions of human periodontal ligament stem cells during periodontitis via the miR-495-3p/HOXC8 axis. Regenerative therapy 7 35509266
2022 Inactivation of KDM5A suppresses growth and enhances chemosensitivity in liver cancer by modulating ROCK1/PTEN/AKT pathway. European journal of pharmacology 6 36566915
2024 Mechanism of KDM5A-mediated H3K4me3 modification in the osteogenic differentiation of mesenchymal stem cells in steroid-induced osteonecrosis of the femoral head. International journal of rheumatic diseases 5 38443978
2024 Epigenetic regulation by KDM5A mediates the effects of prenatal PM2.5 exposure on hippocampal development and synaptic integrity through the Shh signaling pathway. Ecotoxicology and environmental safety 5 38615639
2023 KDM5A noncanonically binds antagonists MLL1/2 to mediate gene regulation and promotes epithelial to mesenchymal transition. Biochimica et biophysica acta. Gene regulatory mechanisms 5 37722486
2022 Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?). BioEssays : news and reviews in molecular, cellular and developmental biology 5 35532219
2021 A computer aided drug discovery based discovery of lead-like compounds against KDM5A for cancers using pharmacophore modeling and high-throughput virtual screening. Proteins 5 34642975
2021 Kdm5a promotes B cell activation in systemic lupus erythematosus via downregulation of A20 by histone modification. Pathology, research and practice 5 34763954
2025 Mechanism of histone demethylase KDM5A in osteoporotic fracture healing through epigenetic regulation of the miR-495/SKP2/Runx2 axis. Molecular medicine (Cambridge, Mass.) 4 39972431
2023 RepID represses megakaryocytic differentiation by recruiting CRL4A-JARID1A at DAB2 promoter. Cell communication and signaling : CCS 4 37612584
2022 Transcriptomic and ChIP-seq Integrative Analysis Identifies KDM5A-Target Genes in Cardiac Fibroblasts. Frontiers in cardiovascular medicine 4 35845066
2025 The KDM5A/HOXA5 axis regulates osteosarcoma progression via activating the Wnt/β-catenin pathway. European journal of medical research 3 40229896
2024 KDM5A/B contribute to HIV-1 latent infection and survival of HIV-1 infected cells. Antiviral research 3 38925368
2022 TSG Targeting KDM5A Affects Osteogenic Differentiation of Bone Mesenchymal Stem Cells Induced by Bone Morphogenetic Protein 2. Journal of healthcare engineering 3 35126937
2020 The histone H3K4 demethylase JARID1A directly interacts with haematopoietic transcription factor GATA1 in erythroid cells through its second PHD domain. Royal Society open science 3 32218938
2020 Exploring the Ligand Preferences of the PHD1 Domain of Histone Demethylase KDM5A Reveals Tolerance for Modifications of the Q5 Residue of Histone 3. ACS chemical biology 3 33314922
2025 Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12. Nature communications 2 40389480
2025 KDM5A, a H3K4me3 demethylase, regulates skin wound healing by promoting M2 macrophage polarization via suppression of Socs1. Frontiers in physiology 2 41164311
2024 Histone demethylase enzymes KDM5A and KDM5B modulate immune response by suppressing transcription of endogenous retroviral elements. bioRxiv : the preprint server for biology 2 39386707
2025 An Intrinsically Disordered Region of Histone Demethylase KDM5A Activates Catalysis Through Interactions With the Nucleosomal Acidic Patch and DNA. Journal of molecular biology 1 40545232
2025 Targeting Endothelial KDM5A to Attenuate Aging and Ameliorate Age-Associated Metabolic Abnormalities. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 41236095
2023 Identifying ligands for the PHD1 finger of KDM5A through high-throughput screening. RSC chemical biology 1 38456036
2022 Generation of a H9 Clonal Cell Line With Inducible Expression of NUP98-KDM5A Fusion Gene in the AAVS1 Safe Harbor Locus. Frontiers in cell and developmental biology 1 35721502
2026 NSUN6 deficiency drives immune suppression in pancreatic cancer via the KDM5A-CCL2-macrophage axis. Gut 0 41571445
2026 KDM5A methylation modulates its genomic demethylase and transcriptional actions. The Journal of biological chemistry 0 41962864
2025 Unbiased analysis of NUP98-KDM5A-induced murine leukemia reveals phenotypic heterogeneity recapitulating human disease subtypes. Experimental hematology 0 40258564
2025 Probiotic DNA epigenetically upregulates epithelial PD-L1 via KDM5A-mediated demethylation to suppress airway allergy by inducing activated Th2 cell apoptosis. International immunopharmacology 0 40398257
2025 HTS Identifies NUP98-KDM5A-PHD3 Domain Ligands with Novel Scaffolds. ACS medicinal chemistry letters 0 40557064
2025 KDM5A: A Master Epigenetic Regulator of Th2 Immunity and Allergic Disease Pathogenesis. Immunology 0 41188062
2025 Loss of KDM5A-mediated H3K4me3 demethylation promotes aberrant neural development by Wnt/β-catenin pathway activation. Cell death & disease 0 41266313
2025 Harnessing the E3 ligase SPOP for targeted degradation of the NUP98::KDM5A fusion oncoprotein. Cell reports 0 41307993
2023 RepID represses megakaryocytic differentiation by recruiting CRL4A-JARID1A at DAB2 promoter. Research square 0 37461562