Affinage

ARID4A

AT-rich interactive domain-containing protein 4A · UniProt P29374

Length
1257 aa
Mass
142.8 kDa
Annotated
2026-06-09
17 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ARID4A (RBBP1) is a multidomain chromatin-associated protein that suppresses aberrant histone trimethylation and acts as a transcriptional coregulator within epigenetic and nuclear-receptor pathways (PMID:17043311, PMID:18728284). In complex with its paralog ARID4B, it binds the Snrpn promoter to maintain genomic imprinting at the Prader-Willi/Angelman domain, controlling H3K9me3, H4K20me3, and DNA methylation at the imprinting center (PMID:17043311). Loss of ARID4A elevates trimethylation of H3K4, H3K9, and H4K20 and deregulates hematopoietic gene expression, driving a myelodysplastic/myeloproliferative disorder that progresses to AML in mice (PMID:18728284), while combined ARID4A/ARID4B deficiency in Sertoli cells causes spermatogenic arrest by phenocopying loss of the androgen receptor and retinoblastoma protein pathways for which ARID4A serves as a transcriptional coactivator (PMID:23487765). Structurally, ARID4A engages chromatin through a PWWP-ARID supramodule whose ARID domain binds dsDNA without sequence preference, while an intramolecular acidic loop L12 acts as a DNA mimic that autoinhibits DNA binding and modulates histone-mark engagement by the chromobarrel domain (PMID:34506790, PMID:35365808); a disease-associated p.His411Asp variant loosens this module, weakens dsDNA binding, and promotes proliferation (PMID:35365808). Beyond chromatin, ARID4A functions as an RNA-binding protein whose ARID domain recognizes a conserved 3'UTR structural element to stabilize metastasis-suppressor mRNAs including MTSS1, TIMP2, Rb1, and PTEN, thereby restraining breast cancer cell migration and invasion (PMID:40066676).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2006 High

    Established ARID4A as a functional partner of ARID4B in an imprinting-regulatory complex, answering how the PWS/AS locus maintains parent-of-origin epigenetic state.

    Evidence Gene-trap KO/knockin mice, ChIP-based histone and DNA methylation assays, and genetic epistasis with Rb and AS-IC mutations

    PMID:17043311

    Open questions at the time
    • Does not define which domain of ARID4A docks at the Snrpn promoter
    • Mechanism linking the ARID4A/ARID4B complex to the histone and DNA methyltransferases that deposit the marks is unresolved
  2. 2006 Medium

    Showed ARID4A is itself an estrogen-responsive gene under isoform-specific ERα/ERβ control, placing it downstream of nuclear-receptor signaling.

    Evidence Microarray, ChIP, and transfection with ER and AF1-deletion mutants plus SRC2 overexpression

    PMID:16873370

    Open questions at the time
    • Does not connect estrogen induction of ARID4A to a specific chromatin or imprinting output
    • Physiological context of ER-driven ARID4A induction untested in vivo
  3. 2008 High

    Demonstrated that ARID4A loss elevates histone trimethylation and deregulates hematopoietic gene expression, defining a tumor-suppressive chromatin-remodeling role linked to leukemogenesis.

    Evidence Arid4a-deficient mice with western blot/IF for histone marks, RT-PCR for Hox and FoxP3 genes, and hematopoietic phenotyping

    PMID:18728284

    Open questions at the time
    • Does not establish whether ARID4A directly recruits or antagonizes a specific methyltransferase
    • Direct versus indirect basis of Hox/FoxP3 deregulation not separated
  4. 2013 High

    Defined ARID4A as a transcriptional coactivator for both AR and RB pathways, explaining its requirement for Sertoli-cell function and blood-testis barrier integrity.

    Evidence Sertoli-cell-specific KO genetics with epistasis to AR-KO and RB-KO models, RT-PCR for target genes, and barrier permeability assays

    PMID:23487765

    Open questions at the time
    • Does not show direct physical contact of ARID4A with AR or RB on target promoters
    • Tissue specificity of the AR/RB coactivator role outside Sertoli cells untested
  5. 2018 Medium

    Resolved the isolated chromobarrel domain structure and showed it alone lacks a DNA-binding surface, indicating histone-mark reading requires additional domains.

    Evidence X-ray crystallography, ITC, and surface-charge analysis of the isolated chromobarrel

    PMID:29408527

    Open questions at the time
    • Negative result confined to the isolated domain
    • Does not test the chromobarrel in the context of the full PWWP-ARID module
  6. 2018 Medium

    Identified ARID4A (and ARID4B) as direct miR-30d targets whose loss enhances prostate cancer cell aggressiveness, framing ARID4A as a post-transcriptionally controlled tumor suppressor.

    Evidence Luciferase 3'UTR reporter, qRT-PCR, and knockout proliferation/migration/invasion assays

    PMID:29797600

    Open questions at the time
    • Does not define the molecular pathway by which ARID4A loss drives invasion
    • In vivo relevance of miR-30d/ARID4A axis not tested
  7. 2021 High

    Provided the mechanistic basis for chromatin engagement, showing the ARID domain binds dsDNA non-specifically and is autoinhibited by an intramolecular acidic loop L12 acting as a DNA mimic.

    Evidence NMR solution structure of the tandem PWWP-ARID domain with NMR titration and L12 deletion mutagenesis

    PMID:34506790

    Open questions at the time
    • Does not establish how L12 autoinhibition is relieved in vivo
    • Functional consequence of L12-H2A-H2B binding for nucleosome targeting unclear
  8. 2022 High

    Defined PWWP and ARID as a single structural/functional supramodule and connected a disease-associated p.His411Asp variant to weakened dsDNA binding and loss of cell-cycle control.

    Evidence 2.05 Å crystal structure with dsDNA-binding assays and flow-cytometry cell-cycle/proliferation readouts in HEK293T cells

    PMID:35365808

    Open questions at the time
    • Does not link the variant to a defined human disease through family or rescue genetics
    • Chromatin-level consequence of weakened DNA binding not measured
  9. 2025 Medium

    Uncovered a non-chromatin function: ARID4A is an RNA-binding protein that stabilizes metastasis-suppressor mRNAs via a conserved 3'UTR element, repositioning it as a post-transcriptional regulator of breast cancer metastasis.

    Evidence RIP, RIP-ChIP, EMSA, mRNA-stability and luciferase assays, plus gain/loss-of-function in vitro and in vivo

    PMID:40066676

    Open questions at the time
    • Does not reconcile how the same ARID domain mediates both DNA and RNA binding
    • Structural basis of 3'UTR element recognition not determined
  10. 2025 Low

    Placed ARID4A in the HERC2 interaction network via a conserved DxDKDxD motif recognized by the HERC2 RLD2 domain, hinting at a role relevant to brain development.

    Evidence Quantitative binding assays and X-ray crystallography of HERC2 RLD2 complexes (preprint)

    PMID:bio_10.1101_2025.09.16.670041

    Open questions at the time
    • ARID4A is one of several listed HERC2 interactors without dedicated functional follow-up
    • Not peer-reviewed; functional consequence of the ARID4A-HERC2 interaction untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ARID4A integrates its chromatin-remodeling, nuclear-receptor coactivator, and mRNA-stabilizing activities into a unified cellular program remains unresolved.
  • No structure of ARID4A bound to a nucleosome or to its target 3'UTR RNA
  • Mechanism coupling histone-mark reading to transcriptional or post-transcriptional output unknown
  • Identity of the methyltransferase activity antagonized by ARID4A not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 2 GO:0003723 RNA binding 1 GO:0042393 histone binding 1 GO:0140110 transcription regulator activity 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005634 nucleus 2
Pathway
R-HSA-1643685 Disease 2 R-HSA-4839726 Chromatin organization 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-8953854 Metabolism of RNA 1
Partners
ARARID4BHERC2RB1
Complex memberships
ARID4A-ARID4B chromatin complex

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 RBBP1/ARID4A interacts physically with RBBP1L1/ARID4B and with the Snrpn promoter, placing both proteins in a protein complex that regulates genomic imprinting at the PWS/AS domain. Combined homozygous deficiency of Rbbp1/Arid4a and heterozygous deficiency of Rbbp1l1/Arid4b reduced trimethylation of histone H4K20 and H3K9 and reduced DNA methylation at the PWS-IC, shifting the maternal allele toward a paternal epigenotype. Mutations of Rbbp1/Arid4a, Rbbp1l1/Arid4b, or Rb suppressed an Angelman syndrome imprinting defect caused by an AS-IC mutation (genetic epistasis). Gene-trap mutagenesis, mouse knockout/knockin, ChIP-based epigenetic analysis (histone methylation, DNA methylation), genetic epistasis with Rb and AS-IC mutations Genes & development High 17043311
2008 Arid4a-deficient mice display increased trimethylation of H3K4, H3K9, and H4K20 in bone marrow, and decreased expression of Hox genes (Hoxb3, Hoxb5, Hoxb6, Hoxb8) and FoxP3, establishing ARID4A as a chromatin remodeling protein that suppresses histone trimethylation and maintains normal hematopoietic gene expression. Loss of Arid4a leads to myelodysplastic/myeloproliferative disorder progressing to AML. Mouse knockout (Arid4a−/−, Arid4a−/−Arid4b+/−), western blotting, immunofluorescence for histone modifications, RT-PCR for downstream gene expression, flow cytometry, histology Journal of the National Cancer Institute High 18728284
2013 ARID4A and ARID4B physically interact with each other. In Sertoli cells, combined deficiency (Arid4a−/−Arid4b+/−) causes spermatogenic arrest and impaired blood-testis barrier, phenocopying Sertoli cell-specific AR and RB knockouts. Molecular analysis identified AR- and RB-responsive genes as downstream targets, indicating ARID4A functions as a transcriptional coactivator for both the androgen receptor (AR) and retinoblastoma protein (RB) pathways. Mouse knockout genetics, genetic epistasis with AR-KO and RB-KO Sertoli cell models, RT-PCR for AR/RB target genes, histology, blood-testis barrier permeability assay Proceedings of the National Academy of Sciences of the United States of America High 23487765
2006 RBBP1 (ARID4A) is transcriptionally regulated by estrogen receptors ERα and ERβ in an isoform-specific manner: ERα drives sustained induction via an Sp1 site in intron 1, while ERβ induction is transient and requires both the Sp1 and estrogen response elements. ChIP showed ERα binding to the intron 1 enhancer is constitutive whereas ERβ binding is transient. RBBP1 induction by both ER isoforms is SRC2-dependent. Deletion of ERα AF1 converted its induction profile to resemble ERβ. Microarray, RT-PCR, chromatin immunoprecipitation (ChIP), transient transfection with ER mutants, stable transfection with AF1 deletion, SRC2 overexpression The Journal of biological chemistry Medium 16873370
2021 The solution structure of the tandem PWWP-ARID domain of RBBP1 (ARID4A) was determined by NMR. The ARID domain interacts with DNA without GC- or AT-rich sequence preference. A long flexible acidic loop L12 within the ARID domain acts as a DNA mimic, binding to the ARID DNA-binding region and inhibiting DNA binding; L12 also binds weakly to the Tudor and chromobarrel domains and more strongly to the histone H2A-H2B heterodimer. Both L12 and DNA enhance chromobarrel binding to H3K4me3 and H4K20me3. NMR structure determination, NMR titration, deletion mutagenesis of loop L12 Journal of molecular biology High 34506790
2022 The crystal structure of the PWWP-ARID tandem supramodule of ARID4A was determined at 2.05 Å, revealing that PWWP and ARID form a structural and functional supramodule. A disease-associated missense variant p.His411Asp (in the ARID domain) causes a less compact conformation and reduces dsDNA-binding ability. The mutation also decreases G0/G1 arrest and promotes cell proliferation in HEK293T cells. X-ray crystallography (2.05 Å), dsDNA-binding assays with wild-type and mutant protein, cell cycle analysis by flow cytometry, cell proliferation assay Molecular psychiatry High 35365808
2018 The crystal structure of the chromo barrel domain of RBBP1 (ARID4A) was determined. ITC assays showed that DNA does not significantly enhance histone H4K20me3 binding by the isolated chromo barrel domain, and surface charge analysis indicated the chromo barrel lacks a typical DNA-binding surface, suggesting this domain alone does not bind DNA. (Negative result: DNA-enhanced H4K20me3 binding requires additional domains beyond the isolated chromo barrel.) X-ray crystallography, isothermal titration calorimetry (ITC), surface charge analysis Biochemical and biophysical research communications Medium 29408527
2025 ARID4A functions as an RNA-binding protein (RBP) that stabilizes mRNAs of metastasis-suppressing genes (MTSS1, TIMP2, Rb1, PTEN) by binding a conserved structural RNA element in their 3'UTRs. The ARID domain of ARID4A is required for mRNA stabilization and metastasis inhibition. Loss of ARID4A promotes breast tumor cell migration and invasion in vitro and in vivo. RNA immunoprecipitation (RIP), RIP-ChIP, mRNA stability assay, EMSA, luciferase assay, gain-of-function and loss-of-function experiments in vitro and in vivo (mouse xenograft or orthotopic model implied), PCR array Cancer medicine Medium 40066676
2018 Both ARID4A and ARID4B are direct targets of miR-30d; miR-30d negatively regulates their mRNA levels. Knockout of ARID4A and/or ARID4B promotes prostate cancer cell proliferation, migration, and invasion in vitro. Luciferase reporter assay for miR-30d targeting of 3'UTR, qRT-PCR, siRNA/CRISPR knockout, proliferation/migration/invasion assays Journal of cellular biochemistry Medium 29797600
2025 HERC2 binds to ARID4A via a conserved 'DxDKDxD' motif in ARID4A that is recognized by the RLD2 domain of HERC2, placing ARID4A as a binding partner in the HERC2 interaction network relevant to brain development. Quantitative binding assays, X-ray crystallography of HERC2 RLD2 domain complexes, sequence conservation analysis bioRxivpreprint Low bio_10.1101_2025.09.16.670041

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The cyst nematode SPRYSEC protein RBP-1 elicits Gpa2- and RanGAP2-dependent plant cell death. PLoS pathogens 125 19714238
2014 Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer. International journal of cancer 101 24382590
2006 Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain. Genes & development 83 17043311
2008 Identification of chromatin remodeling genes Arid4a and Arid4b as leukemia suppressor genes. Journal of the National Cancer Institute 75 18728284
2013 ARID4A and ARID4B regulate male fertility, a functional link to the AR and RB pathways. Proceedings of the National Academy of Sciences of the United States of America 60 23487765
2002 Identification and polymorphism of Plasmodium vivax RBP-1 peptides which bind specifically to reticulocytes. Peptides 28 12535708
2006 Estrogen receptor isoform-specific regulation of the retinoblastoma-binding protein 1 (RBBP1) gene: roles of AF1 and enhancer elements. The Journal of biological chemistry 19 16873370
2018 Downregulation of ARID4A and ARID4B promote tumor progression and directly regulated by microRNA-30d in patient with prostate cancer. Journal of cellular biochemistry 18 29797600
2011 The evolution of the Gp-Rbp-1 gene in Globodera pallida includes multiple selective replacements. Molecular plant pathology 16 22192092
2013 Evolution and variability of Solanum RanGAP2, a cofactor in the incompatible interaction between the resistance protein GPA2 and the Globodera pallida effector Gp-RBP-1. BMC evolutionary biology 8 23601377
2018 Functional haplotypes of ARID4A affect promoter activity and semen quality of bulls. Animal reproduction science 7 30195942
2021 Structural Insight into Chromatin Recognition by Multiple Domains of the Tumor Suppressor RBBP1. Journal of molecular biology 6 34506790
1999 Cytotoxic T lymphocytes that recognize decameric peptide sequences of retinoblastoma binding protein 1 (RBP-1) associated with human breast cancer. British journal of cancer 6 10496363
2022 A novel heterozygous missense variant of the ARID4A gene identified in Han Chinese families with schizophrenia-diagnosed siblings that interferes with DNA-binding activity. Molecular psychiatry 4 35365808
2018 Crystal structure of chromo barrel domain of RBBP1. Biochemical and biophysical research communications 4 29408527
2019 Resonance assignments for the tandem PWWP-ARID domains of human RBBP1. Biomolecular NMR assignments 2 30666492
2025 Arid4a Suppresses Breast Tumor Metastasis by Enhancing MTSS1 Expression via mRNA Stability. Cancer medicine 0 40066676

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