Affinage

KDM5A

Lysine-specific demethylase 5A · UniProt P29375

Length
1690 aa
Mass
192.1 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KDM5A is a JmjC-domain histone demethylase that removes H3K4me2/3 marks to repress transcription at target gene promoters across diverse developmental, metabolic, immune, and circadian programs (PMID:23093672, PMID:26314709). Its catalysis is iron- and oxygen-dependent, such that hypoxia inhibits the enzyme and elevates global and gene-specific H3K4me3 (PMID:20406991), and proceeds through a cysteine (Cys481) adjacent to the αKG/Fe(II) pocket that is targetable by covalent inhibitors (PMID:30392349). Substrate engagement is multilayered: the PHD1 reader domain preferentially binds the unmethylated H3K4 product and allosterically stimulates the catalytic domain, generating positive feedback that spreads demethylation (PMID:25686748, PMID:33621062), while an intrinsically disordered arginine-rich region contacts the H2A/H2B acidic patch and nucleosomal DNA to enable activity on nucleosome substrates (PMID:40545232). KDM5A operates within multiprotein repressive assemblies—the NuRD and SIN3B HDAC complexes (PMID:25190814), a G9a co-repressor complex coordinating H3K9me2 deposition with H3K4me3 removal (PMID:23112189), and the Notch repressor RBP-J (PMID:20231316)—and is recruited to specific loci by sequence-specific factors including E2F4/p130 and the retinoblastoma tumor suppressor (PMID:23093672, PMID:22615382), NF-κB p50 (PMID:27050510), C/EBPβ (PMID:31061100), and GATA1 (PMID:32218938). Beyond classical repression, KDM5A can activate transcription in a demethylase-independent manner by inhibiting HDAC1, as at CLOCK-BMAL1-driven circadian promoters (PMID:21960634). KDM5A is also recruited to DNA double-strand breaks via a noncanonical PAR-binding coiled-coil domain and the histone variant macroH2A1.2, where its H3K4me3 demethylation licenses ZMYND8-NuRD binding and homology-directed repair (PMID:28572115, PMID:34003252). Its abundance is controlled by FBXO22-mediated ubiquitin-proteasomal degradation (PMID:36112263). Loss-of-function in mice produces autism-related behavioral and dendritic phenotypes, establishing KDM5A as a functional ASD gene (PMID:33350388).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2010 High

    Established KDM5A as a bona fide H3K4 demethylase whose enzymatic activity depends on molecular oxygen, explaining how its repressive output is environmentally tunable.

    Evidence In vitro demethylation assays plus siRNA knockdown and ChIP under varied oxygen tension in Beas-2B cells

    PMID:20406991

    Open questions at the time
    • Did not define the genome-wide set of physiological target promoters
    • Oxygen sensitivity threshold relative to cellular hypoxic ranges not fully mapped
  2. 2010 High

    Connected KDM5A's demethylase function to a defined repressive pathway by showing it partners with the Notch effector RBP-J for gene silencing, conserved from Drosophila to mammals.

    Evidence Reciprocal Co-IP, ChIP, and knockdown/rescue in mammalian cells and Drosophila

    PMID:20231316

    Open questions at the time
    • Whether demethylase activity is required at all RBP-J target loci not resolved
    • Structural basis of the KDM5A-RBP-J interaction unknown
  3. 2011 High

    Revealed a demethylase-independent activating mode in which KDM5A inhibits HDAC1 within the CLOCK-BMAL1 complex, showing the enzyme is not exclusively repressive.

    Evidence Co-IP, ChIP, luciferase reporters, and Drosophila lid mutant analysis

    PMID:21960634

    Open questions at the time
    • Molecular mechanism by which KDM5A inhibits HDAC1 not defined
    • Generality of this activating mode beyond circadian promoters unclear at the time
  4. 2012 High

    Placed KDM5A within tumor-suppressor and cell-cycle repression networks by showing recruitment by RB and cooperation with E2F4/p130 to deeply silence cell-cycle genes during differentiation and senescence.

    Evidence Mass spectrometry, ChIP-seq, knockout ES cells, and senescence assays

    PMID:22615382 PMID:23093672

    Open questions at the time
    • How RB/E2F4 physically recruit KDM5A to start sites not mechanistically dissected
    • Relative contribution of demethylase versus scaffold function in repression unresolved
  5. 2012 High

    Defined KDM5A as a member of dedicated co-repressor complexes, coordinating H3K4me3 removal with G9a-mediated H3K9me2 deposition for stable gene silencing.

    Evidence Co-IP, sequential ChIP, and dual knockdowns in erythroid cells

    PMID:23112189

    Open questions at the time
    • Order of events between H3K4 demethylation and H3K9 methylation not established
    • Whether the G9a complex is distinct from NuRD/SIN3B assemblies unclear
  6. 2014 High

    Demonstrated stable association of KDM5A with the NuRD and SIN3B HDAC complexes, linking H3K4 demethylation to deacetylation in conserved repressive machinery.

    Evidence Immunoaffinity purification, density-gradient sedimentation, sequential Co-IP, and C. elegans genetic epistasis

    PMID:25190814

    Open questions at the time
    • Subunit-level architecture of KDM5A within NuRD not resolved
    • Whether complex membership is dynamic across cell types unknown
  7. 2015 High

    Uncovered the allosteric logic of the enzyme: the PHD1 reader binds the unmethylated H3K4 product to stimulate the catalytic domain, creating a feed-forward mechanism for demethylation spreading.

    Evidence NMR structural studies with in vitro demethylase assays on peptide and nucleosome substrates

    PMID:25686748

    Open questions at the time
    • Whether this feedback operates on chromatin in cells not directly shown
    • Quantitative contribution of spreading to genome-wide repression unknown
  8. 2015 High

    Linked KDM5A repression to metabolism by showing it directly silences mitochondrial biogenesis genes including Pgc-1α, with loss restoring respiration and overriding a differentiation block.

    Evidence Kdm5a knockout mouse cells, ChIP, metabolic phenotyping, and PGC-1α rescue

    PMID:26314709

    Open questions at the time
    • How KDM5A is targeted to metabolic gene promoters not defined
    • Reciprocal regulation between mitochondrial state and KDM5A not addressed here
  9. 2017 High

    Extended KDM5A function to genome maintenance by showing it is recruited to double-strand breaks to demethylate H3K4me3, enabling ZMYND8-NuRD recruitment, transcriptional silencing, and homologous recombination.

    Evidence Laser microirradiation, ChIP at DSBs, HR repair assay, and Co-IP

    PMID:28572115

    Open questions at the time
    • At this stage the recruitment mechanism to breaks was not identified
    • Timing relative to other DSB chromatin events unclear
  10. 2018 High

    Solved the structural basis for selective inhibition, identifying active-site Cys481 unique to KDM5A and establishing covalent inhibitors as chemical tools.

    Evidence Co-crystal X-ray structures, demethylase inhibition assays, and dialysis-reversal covalency tests

    PMID:30392349

    Open questions at the time
    • Selectivity over KDM5 paralogs sharing the cysteine not fully resolved
    • In-cell engagement of Cys481 by these inhibitors not quantified
  11. 2019 High

    Established KDM5A as a driver in small-cell lung cancer by repressing NOTCH2 to sustain ASCL1-driven neuroendocrine differentiation, with in vivo CRISPR loss reducing tumorigenesis.

    Evidence CRISPR mouse SCLC model, cell-line knockdown, and in vivo tumor assays

    PMID:31727771

    Open questions at the time
    • Whether catalytic activity is essential for the NOTCH2 repression not isolated
    • Direct versus indirect repression of NOTCH2 not fully distinguished
  12. 2016 High

    Showed KDM5A primes innate immunity by partnering with NF-κB p50 to demethylate H3K4me3 and silence Socs1, with knockout impairing NK cell activation.

    Evidence Kdm5a-/- mouse, Co-IP, ChIP at Socs1, cytokine and infection assays

    PMID:27050510

    Open questions at the time
    • Whether p50 directly recruits KDM5A to Socs1 not structurally confirmed
    • Breadth of immune target loci beyond Socs1 not defined
  13. 2020 Medium

    Refined substrate recognition rules, showing PHD1 reads H3K4me0 with conformational adaptation and that distal H3 tail residues and modifications (including Q5 serotonylation) tune demethylase activity.

    Evidence NMR solution structures, fluorescence polarization, alanine scanning, and high-throughput binding profiling with modified H3 peptides

    PMID:31985200 PMID:33314922 PMID:33621062

    Open questions at the time
    • Physiological relevance of H3Q5 serotonylation sensing in cells not established
    • Crosstalk between distal tail modifications and recruitment factors unknown
  14. 2021 High

    Identified the DSB recruitment mechanism: a noncanonical PAR-binding coiled-coil domain unique to KDM5A together with macroH2A1.2 directs the enzyme to damage sites for repair.

    Evidence Live-cell laser microirradiation, PAR Co-IP, PARP inhibition, macroH2A1.2 knockdown, and HR repair assay

    PMID:34003252

    Open questions at the time
    • Whether PAR binding and macroH2A1.2 act sequentially or in parallel not resolved
    • Structural definition of the PAR-binding coiled-coil not provided
  15. 2022 Medium

    Defined post-translational control of KDM5A abundance through FBXO22-mediated ubiquitin-proteasomal degradation, linking turnover to p16 derepression and reduced metastasis.

    Evidence Ubiquitination assay, Co-IP, ChIP at p16, and xenograft model

    PMID:36112263

    Open questions at the time
    • Signals controlling FBXO22-KDM5A engagement not defined
    • Degron within KDM5A not mapped
  16. 2024 High

    Established KDM5A as a functional autism gene by showing loss-of-function mice exhibit core ASD-related behavioral and dendritic phenotypes with hippocampal transcriptome dysregulation.

    Evidence Forward genetics screen, Kdm5a-/- mouse behavioral battery, dendritic morphology, and RNA-seq with human cohort corroboration

    PMID:33350388

    Open questions at the time
    • Causal target genes driving the neurodevelopmental phenotype not pinpointed
    • Whether catalytic versus scaffold function underlies the phenotype unresolved
  17. 2025 High

    Resolved how KDM5A acts on physiological substrates, showing an intrinsically disordered arginine-rich region binds the nucleosome acidic patch and DNA to enable demethylation of nucleosomes rather than peptides.

    Evidence In vitro nucleosome demethylase assays, crosslinking mass spectrometry, and IDR deletion mutagenesis

    PMID:40545232

    Open questions at the time
    • In-cell requirement of the IDR contacts not demonstrated
    • Integration of IDR-nucleosome binding with PHD1 allostery not modeled

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved when KDM5A acts as a catalytic demethylase versus a non-catalytic scaffold, and how its many recruitment factors, complexes, and post-translational controls are coordinated to select context-specific targets in vivo.
  • No unified model distinguishing demethylase-dependent from scaffold functions across contexts
  • Mechanisms selecting among RBP-J, E2F4, p50, C/EBPβ, GATA1, and other recruiters at given loci unknown
  • Whether catalytic inhibitors phenocopy genetic loss for non-catalytic roles unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0042393 histone binding 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 3 GO:0016491 oxidoreductase activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2 GO:0005694 chromosome 1
Pathway
R-HSA-4839726 Chromatin organization 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1640170 Cell Cycle 2 R-HSA-73894 DNA Repair 2 R-HSA-168256 Immune System 1 R-HSA-9909396 Circadian clock 1
Partners
C/EBPΒCHD4E2F4G9AGATA1MACROH2A1.2RBPJZMYND8
Complex memberships
CLOCK-BMAL1 complexG9a co-repressor complexNuRD complexSIN3B HDAC complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 KDM5A is an H3K4 demethylase that physically interacts with the Notch transcriptional repressor RBP-J and is required for RBP-J-mediated gene silencing; this interaction is conserved in Drosophila and is crucial for Notch-induced growth and tumorigenesis responses. Co-immunoprecipitation, ChIP, functional knockdown/rescue in mammalian cells and Drosophila Genes & development High 20231316
2010 Hypoxia inhibits KDM5A (JARID1A) H3K4 demethylase catalytic activity in an oxygen-tension-dependent manner (oxygen is required as a co-substrate), resulting in global and gene-specific increases in H3K4me3; knockdown of JARID1A largely abolishes the hypoxia-induced H3K4me3 increase, identifying KDM5A as the major H3K4 demethylase in Beas-2B cells. In vitro histone demethylation assay, siRNA knockdown, ChIP, Western blot Cancer research High 20406991
2011 KDM5A (JARID1a) forms a complex with CLOCK-BMAL1, is recruited to the Per2 promoter, inhibits HDAC1 function to increase histone acetylation, and thereby enhances CLOCK-BMAL1 transcriptional activity in a demethylase-independent manner; depletion of JARID1a reduces Per promoter histone acetylation and shortens circadian period. Co-immunoprecipitation, ChIP, siRNA knockdown, luciferase reporter assays, Drosophila lid mutant analysis Science High 21960634
2011 KDM5A (JARID1A) binds to the progesterone receptor (PR) gene upstream regulatory region in a ligand-independent manner and suppresses PR promoter activity through its H3K4 demethylase activity; enzymatically inactive mutant KDM5A fails to suppress PR transcription. ChIP, promoter-reporter assay, overexpression of wild-type vs. catalytic mutant KDM5A, siRNA knockdown The FEBS journal Medium 21348942
2012 KDM5A (Jarid1a) is recruited by the retinoblastoma tumor suppressor to target gene promoters in senescent cells, where it demethylates H3K4 to contribute to silencing of RB target genes; this links KDM5A to a tumor-suppressor network controlling cellular senescence. Quantitative mass spectrometry, ChIP-seq, shRNA knockdown, functional senescence assays PNAS High 22615382
2012 KDM5A co-occupies a large fraction of E2F4 target genes and cooperates with E2F4 to promote H3K4me3 removal and deep repression of cell cycle genes during ES cell differentiation; KDM5A is recruited to transcription start sites independently of E2F4 but p130 (DREAM complex component) occupies common KDM5A/E2F4 targets in terminally differentiated cells. Genome-wide ChIP-seq (location analysis), KDM5A knockout ES cells, quantitative gene-expression analysis PNAS High 23093672
2012 KDM5A (Jarid1a) forms a distinct repressive protein complex with the histone methyltransferase G9a/KMT1C; the coordinate action of G9a-mediated H3K9me2 deposition and KDM5A-mediated H3K4me3 removal is required for maintenance of gene silencing at the embryonic globin locus during development. Co-immunoprecipitation, ChIP, sequential ChIP, knockdown of G9a and Jarid1a in erythroid cells PNAS High 23112189
2014 KDM5A is physically and functionally associated with two histone deacetylase complexes: the SIN3B-containing HDAC complex and the NuRD complex; KDM5A depletion co-regulates hundreds of genes with CHD4 (NuRD catalytic subunit), and the C. elegans homologs of KDM5 and CHD4 function in the same pathway during vulva development. Immunoaffinity purification, sucrose-density gradient sedimentation, sequential co-immunoprecipitation, ChIP, RNAi in C. elegans Journal of Biological Chemistry High 25190814
2015 The PHD1 domain of KDM5A preferentially binds unmethylated H3K4 (the product of KDM5A-mediated demethylation), and this binding allosterically stimulates the catalytic jumonji C domain to remove methyl marks from H3K4me3 on peptide and nucleosome substrates, creating a positive-feedback mechanism for spreading demethylation. NMR-based structural studies, biochemical binding assays, in vitro demethylase activity assays with peptide and nucleosome substrates Nature Communications High 25686748
2015 Loss of Kdm5a restores differentiation in pRB-deficient cells by increasing mitochondrial respiration; KDM5A is a direct transcriptional repressor of metabolic regulatory genes, and activation of mitochondrial biogenesis (via Pgc-1α, a target of KDM5A) is sufficient to override the differentiation block independently of cell cycle exit. Kdm5a knockout mouse cells, Rb1 knockout comparison, mitochondrial oxygen consumption assays, ChIP, gene-expression profiling, PGC-1α overexpression rescue Genes & development High 26314709
2016 KDM5A (Kdm5a) associates with the NF-κB subunit p50 and binds the Socs1 promoter in resting NK cells, leading to H3K4me3 demethylation and repressive chromatin at the Socs1 locus; Kdm5a-deficient mice show impaired NK cell activation with decreased IFN-γ production and increased SOCS1 expression, establishing a role for KDM5A in priming innate immune responses. Kdm5a−/− mouse model, Co-immunoprecipitation (KDM5A-p50 interaction), ChIP (H3K4me3 at Socs1 promoter), cytokine assays, infection model Cell Reports High 27050510
2016 KDM5A inhibits BMP2-induced osteogenic differentiation of mesenchymal stem cells by binding to the Runx2 promoter and demethylating H3K4me3, thereby reducing Runx2 expression; this mechanism is elevated in osteoporosis and its inhibition rescues BMP2-induced bone formation. ChIP assay, KDM5A overexpression/shRNA in MSCs, OVX mouse model, alkaline phosphatase and mineralization assays Cell Death & Disease Medium 27512956
2017 KDM5A is recruited to DNA double-strand break sites where it demethylates H3K4me3; this demethylation is required for ZMYND8-NuRD complex binding to damaged chromatin and for transcriptional silencing and homologous recombination repair at DSBs. Laser microirradiation/live-cell imaging, ChIP at DSB sites, KDM5A knockdown, HR repair assay, Co-IP (ZMYND8-NuRD) Journal of Cell Biology High 28572115
2018 The catalytic domain of KDM5A contains an active-site cysteine (Cys481) near the αKG/Fe(II) binding pocket that is absent in other histone demethylase families; structure-based irreversible inhibitors form a covalent bond with Cys481, and co-crystal structures of the KDM5A catalytic domain with these inhibitors confirmed the binding mode. X-ray crystallography (co-crystal structures), in vitro demethylase inhibition assays, dialysis-reversal experiments confirming covalent vs. non-covalent inhibition Journal of Medicinal Chemistry High 30392349
2018 KDM5A is required for repression of astrocytogenesis in neural progenitor cells; KDM5A occupies the Gfap promoter and its loss increases H3K4 methylation at this locus, promoting astrocyte differentiation; KDM5A protein expression is translationally regulated downstream of eIF4E phosphorylation. KDM5A knockdown/overexpression in NPCs, ChIP (KDM5A and H3K4me3 at Gfap promoter), GFAP reporter assay, eIF4E phosphorylation analysis FASEB Journal Medium 29212818
2019 KDM5A promotes SCLC's neuroendocrine differentiation and proliferation by repressing NOTCH2 and Notch target genes, thereby sustaining ASCL1 expression; KDM5A sgRNA in a CRISPR-based mouse SCLC model decreased tumorigenesis and metastasis, and resulting tumors showed higher NOTCH activity. CRISPR/Cas9 mouse SCLC model (sgRNA co-delivery), KDM5A knockdown in SCLC cell lines, gene-expression analysis, in vivo tumor formation assay Genes & development High 31727771
2019 KDM5A binds directly to the MPC-1 promoter and transcriptionally suppresses MPC-1 expression through H3K4 demethylation, thereby redirecting mitochondrial pyruvate metabolism and promoting pancreatic cancer cell proliferation and invasion. ChIP assay (KDM5A binding at MPC-1 promoter and H3K4me3 levels), KDM5A overexpression/knockdown, in vitro metabolic assays, xenograft mouse model Oncogene Medium 31641207
2019 KDM5A is transactivated by C/EBPβ during adipogenesis; KDM5A then demethylates H3K4me3 at the Wnt6 promoter to repress Wnt6 expression, and KDM5A physically interacts with C/EBPβ to cooperatively inhibit Wnt/β-catenin signaling and promote preadipocyte differentiation. ChIP, co-immunoprecipitation (KDM5A-C/EBPβ interaction), siRNA knockdown, RT-qPCR, immunoblotting Journal of Biological Chemistry Medium 31061100
2020 The PHD1 domain of KDM5A preferentially binds H3K4me0 over methylated states; NMR solution structure of apo and H3-bound PHD1 reveals conformational changes in PHD1 to accommodate H3 in a helical conformation, and post-translational modifications at distal H3 tail positions (residues 14–18) modulate KDM5A-dependent demethylation activity. NMR solution structure determination, fluorescence polarization binding assays, in vitro demethylase activity assays with modified H3 peptides ACS Chemical Biology High 33621062
2020 KDM5A acts as an H3K4me3 demethylase at the miR-495 promoter in prostate cancer cells, repressing miR-495 transcription, which in turn de-represses YTHDF2, leading to m6A-dependent degradation of MOB3B mRNA and promoting cancer progression. ChIP assay (KDM5A at miR-495 promoter, H3K4me3 levels), dual luciferase reporter, PAR-CLIP, Me-RIP, knockdown/overexpression, xenograft mouse model Journal of Experimental & Clinical Cancer Research Medium 33087165
2021 KDM5A is recruited to DNA damage sites via two mechanisms: (1) a noncanonical poly(ADP-ribose) (PAR)-binding coiled-coil domain unique to KDM5A that mediates PAR/PARP interactions, and (2) the histone variant macroH2A1.2; loss of either the PAR-binding region or macroH2A1.2 blocks KDM5A-mediated DNA repair (homology-directed repair) and transcriptional silencing at DSBs. Live-cell imaging (laser microirradiation), Co-IP (KDM5A-PAR interaction), PARP inhibitor treatment, macroH2A1.2 knockdown, HR repair assay Journal of Cell Biology High 34003252
2019 HDAC1 negatively regulates RBPJ occupancy on mitotic chromatin in a KDM5A-dependent manner; KDM5A knockdown or HDAC1 inactivation both increase site-specific RBPJ binding on mitotic chromatin, and KDM5A is required for this increased RBPJ occupancy. HDAC1 knockdown/inactivation, KDM5A knockdown, mitotic chromatin ChIP Nucleic Acids Research Medium 30916347
2014 Decreased JARID1A (KDM5A) occupancy at the PR-A promoter at the onset of human labour correlates with increased H3K4me3 and increased PR-A expression, providing a mechanism for epigenetically regulated progesterone withdrawal that precipitates parturition. Chromatin immunoprecipitation (ChIP) in human myometrial tissue samples, bisulfite sequencing Molecular Human Reproduction Medium 24442343
2020 KDM5A recognizes H3Q5 as a critical determinant for substrate recognition; protein-protein interactions between KDM5A and the distal histone H3 tail (residues 14–18) are required for efficient demethylation; post-translational modifications at this distal epitope modulate KDM5A activity. Alanine scanning mutagenesis of H3 tail, in vitro demethylase activity assays Biochemistry Medium 31985200
2020 The PHD1 domain of KDM5A is tolerant of mutations at H3Q5, including aromatic substitutions, and binds Q5-serotonylated H3 with high affinity, expanding the known histone modification states recognized by this reader domain. PI-SAMDI high-throughput binding assay, fluorescence polarization binding assay, panel of 361 H3 mutant ligands ACS Chemical Biology Medium 33314922
2022 Fbxo22 targets KDM5A for ubiquitin-mediated proteasomal degradation; reduced KDM5A levels result in increased H3K4me3 at the p16 promoter, upregulating p16 and reducing DNA damage and metastasis in triple-negative breast cancer. Ubiquitination assay, Co-immunoprecipitation, ChIP (H3K4me3), KDM5A overexpression/knockdown, in vivo xenograft Cell Biology and Toxicology Medium 36112263
2023 KDM5A physically interacts with the MLL1 and MLL2 histone methyltransferases and their scaffold protein WDR5, acting as a transcriptional activator at mesenchymal gene promoters by inhibiting HDAC activity and increasing H3K18ac, while acting as a classical repressor at the E-cadherin promoter through H3K4me3 demethylation. ChIP (co-occupancy of KDM5A with MLLs), Co-immunoprecipitation (KDM5A-MLL1/2/WDR5 interaction), H3K18ac ChIP, histone demethylase assay Biochimica et Biophysica Acta. Gene Regulatory Mechanisms Medium 37722486
2023 KDM5A (JARID1A) directly interacts with the haematopoietic transcription factor GATA1 through its second PHD domain (PHD2) in erythroid cells. Co-immunoprecipitation, pulldown assay mapping PHD2 as the interaction domain Royal Society Open Science Medium 32218938
2023 RepID recruits the CRL4A E3 ubiquitin ligase complex together with KDM5A (JARID1A) to the DAB2 promoter to repress it during megakaryocyte proliferation; dissociation of this complex during MK differentiation leads to euchromatinization of the DAB2 promoter. Co-immunoprecipitation, proximity ligation assay (CRL4A-KDM5A interaction), ChIP-qPCR (KDM5A/CRL4A at DAB2 promoter), subcellular fractionation Cell Communication and Signaling Medium 37612584
2024 KDM5A suppresses HIV-1 Tat/LTR-mediated transcription in latently infected cells by demethylating H3K4me3 at the HIV-1 5' LTR promoter; KDM5 inhibition (JQKD82) increases H3K4me3 at the LTR and reactivates latent HIV-1. KDM5A/B deletion in HIV-1 latent cells, KDM5 inhibitor treatment, H3K4me3 ChIP at HIV-1 LTR, viral reactivation assay, patient PBMC ex vivo assay Antiviral Research Medium 38925368
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 are necessary for KDM5A catalytic activity on nucleosome substrates. In vitro demethylase activity assays on nucleosome substrates, cross-linking mass spectrometry (binding interface mapping), IDR deletion mutagenesis Journal of Molecular Biology High 40545232
2024 KDM5A loss-of-function in knock-out mice causes ASD-related phenotypes including vocalization deficits, repetitive behaviors, sociability deficits, and abnormal dendritic morphogenesis, establishing KDM5A as a functional ASD gene; loss of KDM5A results in dysregulation of the hippocampal transcriptome. Forward genetics screen in mice, Kdm5a−/− knockout mouse model, behavioral testing battery, dendritic morphology analysis, RNA-seq eLife High 33350388
2022 Mitochondrial dysfunction induced by amyloid-beta in neural progenitors causes KDM5A protein degradation; since KDM5A also binds and activates neuronal differentiation genes, its loss inhibits adult hippocampal neurogenesis, placing KDM5A as a mediator of retrograde mitochondrial signaling to the nucleus. Neural progenitor Aβ treatment model, proteomic analysis, KDM5A ChIP at neuronal gene promoters, functional differentiation assays, Kdm5a knockout comparison Experimental & Molecular Medicine Medium 36056186
2024 KDM5A deficiency suppresses expression of KRAB-ZNF genes (independently of its catalytic activity, since pan-KDM5 catalytic inhibitor CPI-455 does not recapitulate this effect), leading to de-repression of endogenous retroviruses (ERVs), increased dsRNA levels and activation of immune response genes; KDM5A co-immunoprecipitates with the NuRD complex. KDM5A/B knockout cell lines, RNA-seq, ATAC-seq, H3K4me3 ChIP-seq, KDM5 catalytic inhibitor (CPI-455), dTAG-inducible KDM5A degradation, Co-IP (KDM5A-NuRD) bioRxivpreprint Medium 39386707

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.) 182 21960634
2010 Histone demethylase KDM5A is an integral part of the core Notch-RBP-J repressor complex. Genes & development 152 20231316
2017 Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair. The Journal of cell biology 142 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
2019 The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis. Genes & development 105 31727771
2010 Hypoxia induces trimethylated H3 lysine 4 by inhibition of JARID1A demethylase. Cancer research 103 20406991
2015 Histone demethylase KDM5A is regulated by its reader domain through a positive-feedback mechanism. Nature communications 101 25686748
2006 Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. Genes, chromosomes & cancer 101 16419055
2020 Activation of the KDM5A/miRNA-495/YTHDF2/m6A-MOB3B axis facilitates prostate cancer progression. Journal of experimental & clinical cancer research : CR 87 33087165
2016 KDM5A controls bone morphogenic protein 2-induced osteogenic differentiation of bone mesenchymal stem cells during osteoporosis. Cell death & disease 87 27512956
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 75 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 68 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 66 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 61 30650517
2019 A novel KDM5A/MPC-1 signaling pathway promotes pancreatic cancer progression via redirecting mitochondrial pyruvate metabolism. Oncogene 50 31641207
2020 Enhancing KDM5A and TLR activity improves the response to immune checkpoint blockade. Science translational medicine 46 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 44 33499904
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 43 34372882
2020 KDM5A mutations identified in autism spectrum disorder using forward genetics. eLife 42 33350388
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
2017 KDM5A promotes proliferation and EMT in ovarian cancer and closely correlates with PTX resistance. Molecular medicine reports 41 28714030
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
2021 Poly(ADP-ribose) binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions. The Journal of cell biology 29 34003252
2020 Effect of histone demethylase KDM5A on the odontogenic differentiation of human dental pulp cells. Bioengineered 29 32208897
2020 Molecular mechanisms of KDM5A in cellular functions: Facets during development and disease. Experimental cell research 28 33010254
2019 Human models of NUP98-KDM5A megakaryocytic leukemia in mice contribute to uncovering new biomarkers and therapeutic vulnerabilities. Blood advances 28 31698461
2018 Histone demethylase KDM5A inhibits glioma cells migration and invasion by down regulating ZEB1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 28 29324315
2022 Inhibition of KDM5A attenuates cisplatin-induced hearing loss via regulation of the MAPK/AKT pathway. Cellular and molecular life sciences : CMLS 25 36396833
2022 Drawing a line between histone demethylase KDM5A and KDM5B: their roles in development and tumorigenesis. Experimental & molecular medicine 25 36509829
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
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 22 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
2021 lncRNA NEAT1 facilitates the progression of colorectal cancer via the KDM5A/Cul4A and Wnt signaling pathway. International journal of oncology 20 34109988
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
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 16 30916347
2022 KDM5A Inhibits Antitumor Immune Responses Through Downregulation of the Antigen-Presentation Pathway in Ovarian Cancer. Cancer immunology research 15 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
2023 Domain architecture and protein-protein interactions regulate KDM5A recruitment to the chromatin. Epigenetics 11 37838974
2017 Repair of Calvarial Bone Defect Using Jarid1a-Knockdown Bone Mesenchymal Stem Cells in Rats. Tissue engineering. Part A 11 28903624
2023 Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity. Science advances 10 37992166
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
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
2023 KDM5A noncanonically binds antagonists MLL1/2 to mediate gene regulation and promotes epithelial to mesenchymal transition. Biochimica et biophysica acta. Gene regulatory mechanisms 7 37722486
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
2025 Mechanism of histone demethylase KDM5A in osteoporotic fracture healing through epigenetic regulation of the miR-495/SKP2/Runx2 axis. Molecular medicine (Cambridge, Mass.) 6 39972431
2022 Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?). BioEssays : news and reviews in molecular, cellular and developmental biology 6 35532219
2022 Inactivation of KDM5A suppresses growth and enhances chemosensitivity in liver cancer by modulating ROCK1/PTEN/AKT pathway. European journal of pharmacology 6 36566915
2021 Kdm5a promotes B cell activation in systemic lupus erythematosus via downregulation of A20 by histone modification. Pathology, research and practice 6 34763954
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
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
2024 KDM5A/B contribute to HIV-1 latent infection and survival of HIV-1 infected cells. Antiviral research 4 38925368
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
2026 NSUN6 deficiency drives immune suppression in pancreatic cancer via the KDM5A-CCL2-macrophage axis. Gut 3 41571445
2025 The KDM5A/HOXA5 axis regulates osteosarcoma progression via activating the Wnt/β-catenin pathway. European journal of medical research 3 40229896
2025 Transcriptional and epigenetic rewiring by the NUP98::KDM5A fusion oncoprotein directly activates CDK12. Nature communications 3 40389480
2025 KDM5A, a H3K4me3 demethylase, regulates skin wound healing by promoting M2 macrophage polarization via suppression of Socs1. Frontiers in physiology 3 41164311
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 KDM5A: A Master Epigenetic Regulator of Th2 Immunity and Allergic Disease Pathogenesis. Immunology 2 41188062
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
2025 Harnessing the E3 ligase SPOP for targeted degradation of the NUP98::KDM5A fusion oncoprotein. Cell reports 1 41307993
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 FBXO39 knockdown promotes spermatogenesis impairment by inducing mitochondrial dysfunction and ferroptosis via inhibiting KDM5A ubiquitination and regulating H3K4me3 demethylation. Cell biology and toxicology 0 41781602
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 Loss of KDM5A-mediated H3K4me3 demethylation promotes aberrant neural development by Wnt/β-catenin pathway activation. Cell death & disease 0 41266313
2024 Expression and clinical significance of KDM5A, KDM5B, and FOXO1 in endometrial cancer. Polish journal of pathology : official journal of the Polish Society of Pathologists 0 39166517
2023 RepID represses megakaryocytic differentiation by recruiting CRL4A-JARID1A at DAB2 promoter. Research square 0 37461562

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