{"gene":"ARID4B","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2006,"finding":"RBBP1/ARID4A interacts physically with RBBP1L1/ARID4B and with the Snrpn promoter, and combined deficiency of Arid4a and Arid4b alters epigenetic modifications (reduced trimethylation of H4K20 and H3K9, reduced DNA methylation) at the PWS-IC, changing the maternal allele toward a more paternal epigenotype; mutations in Arid4a, Arid4b, or Rb suppressed an Angelman syndrome imprinting defect caused by a mutation at the AS-IC.","method":"Gene trap mutagenesis, gene knockout mice, western blotting, immunofluorescence, co-immunoprecipitation/promoter interaction assays, genetic epistasis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetics, epistasis, biochemical interaction, chromatin modification assays) in a single rigorous study","pmids":["17043311"],"is_preprint":false},{"year":2008,"finding":"Arid4a-deficient mice progressed from ineffective hematopoiesis to CMML-like myeloproliferative disorder to AML; haploinsufficiency of Arid4b dramatically accelerated AML development (10/12 double-mutant mice vs 5/42 Arid4a-/- alone). Loss of Arid4a increased histone trimethylation of H3K4, H3K9, and H4K20 in bone marrow, and decreased expression of Hox genes (Hoxb3, b5, b6, b8) and FoxP3.","method":"Mouse knockout/haploinsufficiency models, complete blood counts, flow cytometry, histology, RT-PCR, western blotting, immunofluorescence","journal":"Journal of the National Cancer Institute","confidence":"High","confidence_rationale":"Tier 2 — clean KO/haploinsufficiency with defined leukemic phenotype plus molecular mechanism (histone methylation changes, downstream gene expression), replicated across two genotypes","pmids":["18728284"],"is_preprint":false},{"year":2012,"finding":"ARID4B physically interacts with breast cancer metastasis suppressor BRMS1 and with histone deacetylase complex members mSIN3A and mSDS3; allelic variants of Arid4b show differential binding to these HDAC complex members. Ectopic Arid4b expression promoted primary tumor growth and increased cell migration/invasion, while shRNA-mediated knockdown reduced pulmonary metastases and downregulated the Tpx2 gene network regulating cell cycle and mitotic spindle biology.","method":"Co-immunoprecipitation, shRNA knockdown in vivo (mouse MMTV-PyMT model), ectopic overexpression, in vitro migration/invasion assays, gene expression profiling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP for protein interactions, combined with in vivo KD showing defined metastatic phenotype and gene network changes","pmids":["22693453"],"is_preprint":false},{"year":2013,"finding":"ARID4A and ARID4B physically interact with each other; ARID4A is a retinoblastoma (RB)-binding protein. In Sertoli cells, ARID4A and ARID4B function as transcriptional coactivators for androgen receptor (AR) and RB, regulating downstream AR- and RB-responsive genes. Combined deficiency causes spermatogenic arrest, impaired blood-testis barrier, and seminal vesicle agenesis/hypodysplasia, phenocopying Sertoli cell-specific AR and RB knockouts.","method":"Mouse knockout/haploinsufficiency models, physical interaction assays (co-IP), gene expression analysis of AR/RB downstream targets, histology, blood-testis barrier permeability assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — physical interaction demonstrated, combined with genetic epistasis (phenocopy of AR/RB knockouts) and downstream target analysis","pmids":["23487765"],"is_preprint":false},{"year":2013,"finding":"miR-290-3p directly targets the 3' UTR of Arid4b mRNA (confirmed by luciferase reporter assay), suppressing ARID4B expression and thereby suppressing breast cancer progression; miR-290 upregulation also elevated estrogen receptor levels, increasing apoptosis.","method":"miRNA microarray, luciferase reporter assay, in vivo tumor/metastasis models, pathway analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase reporter validates direct miR-290-3p targeting of ARID4B 3'UTR; single lab","pmids":["23447578"],"is_preprint":false},{"year":2015,"finding":"ARID4B functions as a coactivator of androgen receptor (AR) in Sertoli cells and is required for optimal transcriptional activation of reproductive homeobox 5 (Rhox5), an AR target gene. Sertoli cell-specific Arid4b knockout mice are completely infertile with Sertoli cell-only phenotype, germ cell loss, and spermatogenic arrest at the round spermatid stage; Sertoli cell maturation is delayed.","method":"Sertoli cell-specific conditional knockout mice, histology, immunofluorescence, gene expression analysis, AR coactivation assay","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with defined phenotype plus mechanistic coactivator function demonstrated for AR/Rhox5","pmids":["26258622"],"is_preprint":false},{"year":2017,"finding":"In Sertoli cell-specific Arid4b knockout testes, ARID4B ablation causes abnormal Sertoli cell detachment from the basement membrane during the gonocyte-to-SSC transition, failure to establish the stem cell niche, gonocyte apoptosis, and impaired SSC self-renewal. ARID4B regulates downstream niche genes including gap junction protein alpha-1, KIT ligand, AMH, GDNF, inhibin alpha/beta, and Cyp26b1.","method":"Sertoli cell-specific conditional knockout mice, gene expression profiling, histology, cell fate analysis","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined cellular phenotype (niche failure) plus identification of downstream effector network","pmids":["28207192"],"is_preprint":false},{"year":2019,"finding":"PTEN inhibits expression of ARID4B; ARID4B acts as a transcriptional activator of PI3K subunit genes PIK3CA and PIK3R2 by binding their promoters; reciprocal binding of ARID4B and histone H1 to PIK3CA and PIK3R2 promoters modulates chromatin condensation. ARID4B is required for prostate tumorigenesis specifically when PTEN is deficient, defining a PTEN-ARID4B-PI3K axis.","method":"Chromatin immunoprecipitation (ChIP), promoter binding assays, loss-of-function experiments, gene expression analysis, in vivo tumorigenesis models, patient data analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — ChIP validates direct promoter binding, epistasis established by PTEN-deficiency dependence, multiple orthogonal methods","pmids":["31551414"],"is_preprint":false},{"year":2020,"finding":"ARID4B is critical for mouse embryonic stem cell differentiation toward mesodermal and endodermal lineages. Arid4b-deficient mESCs self-renew normally but fail to upregulate meso/endodermal gene expression programs. ARID4B physically and functionally interacts with HDAC1 (but not HDAC2) within the SIN3A complex. ARID4B deficiency leads to increased H3K27me3 and reduced H3K27Ac at key developmental gene loci, while a subset of regions gain H3K27Ac.","method":"Pooled epigenetic shRNA screen, conditional knockout mESCs, differentiation assays, co-immunoprecipitation, ChIP-seq for H3K27me3/H3K27Ac, gene expression profiling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — functional screen, KO differentiation phenotype, physical interaction with HDAC1, chromatin modification mapping via ChIP-seq, multiple orthogonal methods","pmids":["33454011"],"is_preprint":false},{"year":2018,"finding":"miR-30d directly regulates ARID4B (and ARID4A) expression in prostate cancer; mRNA expression of miR-30d is significantly negatively correlated with ARID4B. Knockout of ARID4B promoted prostate cancer cell proliferation, migration, and invasion in vitro, supporting a tumor suppressor function.","method":"miRNA-mRNA correlation in patient tissues, in vitro knockout, proliferation/migration/invasion assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — correlation-based miRNA targeting without direct luciferase validation; functional KO data supports tumor suppressor role","pmids":["29797600"],"is_preprint":false},{"year":2018,"finding":"miR-519b-3p directly binds the 3' UTR of ARID4B mRNA and negatively regulates its expression; overexpression of miR-519b-3p enhanced responsiveness to chemoradiation in rectal cancer cells in an ARID4B-dependent manner.","method":"Luciferase reporter assay, overexpression/knockdown in vitro, patient tissue correlation","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2/3 — luciferase reporter confirms direct 3'UTR targeting; functional rescue confirms ARID4B dependence; single lab","pmids":["29477868"],"is_preprint":false},{"year":2020,"finding":"Circ-SMARCA5 functions as a tumor suppressor in colorectal cancer by sponging miR-93-3p (predicted as miR-39-3p in abstract), thereby upregulating ARID4B expression; this axis inhibits CRC cell proliferation, migration, and invasion in vitro and tumor progression in vivo.","method":"qRT-PCR, luciferase reporter assay, overexpression, CCK-8/wound healing/Transwell assays, xenograft model","journal":"Digestive and liver disease","confidence":"Medium","confidence_rationale":"Tier 3 — luciferase reporter validates miRNA-ARID4B interaction; functional rescue confirms pathway; single lab","pmids":["32807692"],"is_preprint":false},{"year":2021,"finding":"ARID4B knockdown in human glioma cells suppressed PI3K/AKT/mTOR pathway components (p-mTOR, p-PI3K, p-AKT), caused G1 phase arrest by downregulating Cyclin D1, increased HDAC1 expression leading to elevated acetyl-p53 and acetyl-H3 levels, and induced apoptosis; it also reduced glioma cell migration and invasion.","method":"Lentiviral shRNA knockdown, western blotting, flow cytometry (cell cycle/apoptosis), proliferation assay, migration/invasion assay","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, KD with defined signaling phenotype but pathway placement inferred from downstream markers without reconstitution","pmids":["33732001"],"is_preprint":false},{"year":2021,"finding":"Taurine promotes protein synthesis and proliferation of C2C12 myoblast cells through the PI3K-ARID4B-mTOR pathway; ARID4B expression is induced by taurine in a PI3K-dependent manner. ARID4B binds to the -4368 to -4591 bp site of the mTOR promoter (confirmed by ChIP-PCR), promoting H3K27ac (but not H3K27me3) at this site, and ARID4B knockdown abolishes taurine-stimulated mTOR expression and mTOR phosphorylation.","method":"siRNA knockdown, CRISPR/dCas9 gene activation, ChIP-PCR and ChIP-qPCR, PI3K inhibitor (LY294002), western blotting, proliferation assay","journal":"The British journal of nutrition","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrates direct promoter binding; ARID4B KD/activation epistasis places it in PI3K→ARID4B→mTOR axis; single lab","pmids":["34881695"],"is_preprint":false}],"current_model":"ARID4B is a chromatin-associated protein that physically interacts with ARID4A/RB and operates within the SIN3A-HDAC1 complex to regulate histone modifications (H3K27ac, H3K27me3, H3K4me3, H3K9me3, H4K20me3) at developmental and oncogenic loci; it acts as a transcriptional coactivator for androgen receptor (AR) and RB in Sertoli cells (driving spermatogenesis and niche establishment), directly binds and activates the PIK3CA/PIK3R2 promoters to sustain PI3K/AKT signaling downstream of PTEN loss in prostate cancer, and is required for mesoderm/endoderm differentiation of embryonic stem cells, while being post-transcriptionally regulated by multiple miRNAs (miR-290-3p, miR-30d, miR-519b-3p) that target its 3'UTR."},"narrative":{"teleology":[{"year":2006,"claim":"The question of whether ARID4B participates in epigenetic regulation of genomic imprinting was answered: combined Arid4a/Arid4b deficiency altered histone methylation and DNA methylation at the PWS imprinting center, establishing both proteins as chromatin regulators of imprinted loci acting through RB.","evidence":"Gene-trap and knockout mice with co-IP, chromatin modification assays, and genetic epistasis with AS-IC mutation","pmids":["17043311"],"confidence":"High","gaps":["Whether ARID4B directly binds the PWS-IC or acts indirectly through RB","Structural basis of ARID4A–ARID4B interaction","Whether ARID4B has independent functions at imprinted loci apart from ARID4A"]},{"year":2008,"claim":"Whether ARID4B cooperates with ARID4A in tumor suppression was resolved: Arid4b haploinsufficiency dramatically accelerated the progression from myeloproliferative disorder to AML in Arid4a-null mice, linking both proteins to hematopoietic homeostasis via histone methylation of Hox gene loci.","evidence":"Mouse knockout/haploinsufficiency models with histology, flow cytometry, and histone mark analysis in bone marrow","pmids":["18728284"],"confidence":"High","gaps":["Whether ARID4B loss alone is sufficient for leukemogenesis","Direct genomic targets of ARID4B in hematopoietic progenitors","Mechanism by which histone trimethylation changes regulate Hox gene expression"]},{"year":2012,"claim":"The molecular complex context of ARID4B was clarified: ARID4B physically interacts with BRMS1, mSIN3A, and mSDS3, placing it in the SIN3A–HDAC complex, and its expression promotes breast cancer metastasis through the Tpx2 gene network.","evidence":"Reciprocal co-IP for protein interactions, shRNA knockdown in MMTV-PyMT mouse model, gene expression profiling","pmids":["22693453"],"confidence":"High","gaps":["Whether ARID4B directly regulates Tpx2 transcription or acts indirectly","Allelic variant effects on HDAC complex stoichiometry in vivo"]},{"year":2013,"claim":"ARID4B was established as a transcriptional coactivator for androgen receptor and RB in Sertoli cells: combined Arid4a/Arid4b deficiency phenocopied AR and RB knockouts, causing spermatogenic arrest and blood–testis barrier defects.","evidence":"Mouse knockout models, co-IP, AR/RB target gene expression analysis, histology and barrier permeability assays","pmids":["23487765"],"confidence":"High","gaps":["Whether ARID4B coactivator function depends on its ARID domain DNA binding","Whether ARID4B acts as coactivator in tissues other than Sertoli cells"]},{"year":2013,"claim":"Post-transcriptional regulation of ARID4B was demonstrated: miR-290-3p directly targets the ARID4B 3'UTR, suppressing its expression and thereby inhibiting breast cancer progression.","evidence":"Luciferase reporter assay for direct 3'UTR targeting, in vivo tumor/metastasis models","pmids":["23447578"],"confidence":"Medium","gaps":["Physiological contexts in which miR-290-3p regulates ARID4B beyond breast cancer","Quantitative contribution of miR-290-3p versus other miRNAs to ARID4B regulation"]},{"year":2015,"claim":"The cell-autonomous requirement for ARID4B in male fertility was defined: Sertoli cell-specific Arid4b knockout caused complete infertility with spermatogenic arrest, confirming ARID4B as essential for AR coactivation of Rhox5 and Sertoli cell maturation.","evidence":"Sertoli cell-specific conditional knockout mice, histology, AR coactivation assay","pmids":["26258622"],"confidence":"High","gaps":["Whether ARID4B binds Rhox5 regulatory regions directly","Genome-wide AR-dependent targets requiring ARID4B coactivation in Sertoli cells"]},{"year":2017,"claim":"ARID4B's role was extended from spermatogenesis to stem cell niche establishment: its loss in Sertoli cells caused failure to establish the spermatogonial stem cell niche, with defective expression of niche factors (GDNF, KIT ligand, gap junction proteins).","evidence":"Sertoli cell-specific conditional knockout, gene expression profiling, cell fate analysis","pmids":["28207192"],"confidence":"High","gaps":["Whether ARID4B directly binds niche gene promoters or acts through intermediate regulators","Whether ARID4B regulates stem cell niches in other tissues"]},{"year":2018,"claim":"Additional miRNA regulators of ARID4B were identified: miR-519b-3p directly binds ARID4B 3'UTR to modulate chemoradiation sensitivity in rectal cancer, and miR-30d expression negatively correlates with ARID4B in prostate cancer.","evidence":"Luciferase reporter assays (miR-519b-3p), miRNA-mRNA correlation and functional knockout (miR-30d)","pmids":["29477868","29797600"],"confidence":"Medium","gaps":["miR-30d targeting of ARID4B lacks direct luciferase validation","Relative contribution of different miRNAs to ARID4B protein levels in individual cancer types"]},{"year":2019,"claim":"The mechanism by which ARID4B sustains PI3K/AKT signaling in PTEN-deficient tumors was resolved: ARID4B directly binds PIK3CA and PIK3R2 promoters, competing with histone H1 to maintain open chromatin, and is specifically required for prostate tumorigenesis when PTEN is lost.","evidence":"ChIP for direct promoter binding, loss-of-function epistasis with PTEN, in vivo tumorigenesis models, patient data","pmids":["31551414"],"confidence":"High","gaps":["Whether ARID4B–histone H1 competition is a general mechanism at other ARID4B targets","Structural basis for ARID4B promoter recognition at PIK3CA/PIK3R2"]},{"year":2020,"claim":"ARID4B's role in pluripotent cell differentiation was established: it is required for mesoderm/endoderm lineage commitment of mESCs, physically and functionally interacts with HDAC1 (not HDAC2) within SIN3A, and its loss causes redistribution of H3K27me3/H3K27ac at developmental loci.","evidence":"Pooled epigenetic shRNA screen, conditional knockout mESCs, co-IP, ChIP-seq for H3K27me3/H3K27ac","pmids":["33454011"],"confidence":"High","gaps":["Why ARID4B selectively interacts with HDAC1 but not HDAC2","How ARID4B loss both increases and decreases H3K27ac at different loci","Identity of direct ARID4B-bound genomic sites genome-wide"]},{"year":2021,"claim":"ARID4B was shown to directly activate the mTOR promoter by promoting H3K27ac at a specific upstream site, placing it as a chromatin effector in the PI3K→ARID4B→mTOR signaling axis in myoblasts.","evidence":"ChIP-PCR/ChIP-qPCR for mTOR promoter binding, siRNA knockdown and dCas9 activation epistasis, PI3K inhibitor treatment","pmids":["34881695"],"confidence":"Medium","gaps":["Whether ARID4B-mediated mTOR promoter activation operates in cell types beyond myoblasts","Whether HDAC1/SIN3A complex is involved at the mTOR promoter","Mechanism by which PI3K activity induces ARID4B expression"]},{"year":null,"claim":"A genome-wide map of direct ARID4B binding sites, the structural basis for its ARID domain specificity, and whether its coactivator versus repressor functions are context-dependent or reflect distinct complex compositions remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No genome-wide ARID4B ChIP-seq in any cell type","No structural model of ARID4B or its ARID domain bound to DNA","Mechanism determining whether ARID4B promotes or removes H3K27ac at specific loci"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,5,7,8,13]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,8,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[7,13]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,8]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,8,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,5,7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,12,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,7]}],"complexes":["SIN3A-HDAC1 complex"],"partners":["ARID4A","RB1","HDAC1","SIN3A","BRMS1","AR","SDS3"],"other_free_text":[]},"mechanistic_narrative":"ARID4B is a chromatin-regulatory protein that operates within the SIN3A–HDAC1 complex to modulate histone modifications—including H3K27ac, H3K27me3, H3K4me3, H3K9me3, and H4K20me3—at developmental, imprinted, and oncogenic loci, thereby controlling transcriptional programs required for embryonic stem cell differentiation toward mesoderm/endoderm lineages, genomic imprinting at the PWS/AS locus, and hematopoietic homeostasis [PMID:33454011, PMID:17043311, PMID:18728284]. ARID4B physically interacts with ARID4A and RB and functions as a transcriptional coactivator for androgen receptor in Sertoli cells, where it is essential for spermatogenesis, blood–testis barrier integrity, and establishment of the spermatogonial stem cell niche [PMID:23487765, PMID:26258622, PMID:28207192]. In PTEN-deficient prostate cancer, ARID4B directly binds the PIK3CA and PIK3R2 promoters to sustain PI3K/AKT signaling, and it similarly activates the mTOR promoter by promoting H3K27 acetylation, establishing ARID4B as a chromatin-dependent transcriptional activator of the PI3K–AKT–mTOR axis [PMID:31551414, PMID:34881695]. Arid4b haploinsufficiency cooperates with Arid4a loss to accelerate acute myeloid leukemia in mice, and its expression is post-transcriptionally regulated by multiple miRNAs including miR-290-3p and miR-519b-3p [PMID:18728284, PMID:23447578, PMID:29477868]."},"prefetch_data":{"uniprot":{"accession":"Q4LE39","full_name":"AT-rich interactive domain-containing protein 4B","aliases":["180 kDa Sin3-associated polypeptide","Sin3-associated polypeptide p180","Breast cancer-associated antigen BRCAA1","Histone deacetylase complex subunit SAP180","Retinoblastoma-binding protein 1-like 1"],"length_aa":1312,"mass_kda":147.8,"function":"Acts as a transcriptional repressor (PubMed:12724404). May function in the assembly and/or enzymatic activity of the Sin3A corepressor complex or in mediating interactions between the complex and other regulatory complexes (PubMed:12724404). Plays a role in the regulation of epigenetic modifications at the PWS/AS imprinting center near the SNRPN promoter, where it might function as part of a complex with RB1 and ARID4A. Involved in spermatogenesis, together with ARID4A, where it functions as a transcriptional coactivator for AR (androgen receptor) and enhances expression of genes required for sperm maturation. Regulates expression of the tight junction protein CLDN3 in the testis, which is important for integrity of the blood-testis barrier. Plays a role in myeloid homeostasis where it regulates the histone methylation state of bone marrow cells and expression of various genes involved in hematopoiesis. May function as a leukemia suppressor (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q4LE39/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARID4B","classification":"Not Classified","n_dependent_lines":111,"n_total_lines":1208,"dependency_fraction":0.09188741721854304},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SLC25A17","stoichiometry":10.0},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2},{"gene":"RBBP4","stoichiometry":0.2},{"gene":"SNX5","stoichiometry":0.2},{"gene":"TOP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ARID4B","total_profiled":1310},"omim":[{"mim_id":"609696","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 4B; ARID4B","url":"https://www.omim.org/entry/609696"},{"mim_id":"608250","title":"SDS3 HOMOLOG, SIN3A COREPRESSOR COMPLEX COMPONENT; SUDS3","url":"https://www.omim.org/entry/608250"},{"mim_id":"607776","title":"SIN3 TRANSCRIPTION REGULATOR FAMILY MEMBER A; SIN3A","url":"https://www.omim.org/entry/607776"},{"mim_id":"180201","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 4A; ARID4A","url":"https://www.omim.org/entry/180201"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARID4B"},"hgnc":{"alias_symbol":["BCAA","BRCAA1","SAP180"],"prev_symbol":["RBP1L1"]},"alphafold":{"accession":"Q4LE39","domains":[{"cath_id":"2.30.30","chopping":"15-130","consensus_level":"medium","plddt":85.4662,"start":15,"end":130},{"cath_id":"2.30.30.140","chopping":"168-260","consensus_level":"medium","plddt":84.9639,"start":168,"end":260},{"cath_id":"1.10.150.60","chopping":"267-271_304-407","consensus_level":"medium","plddt":88.5684,"start":267,"end":407},{"cath_id":"2.30.30.140","chopping":"574-628","consensus_level":"high","plddt":90.8529,"start":574,"end":628}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4LE39","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q4LE39-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q4LE39-F1-predicted_aligned_error_v6.png","plddt_mean":55.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARID4B","jax_strain_url":"https://www.jax.org/strain/search?query=ARID4B"},"sequence":{"accession":"Q4LE39","fasta_url":"https://rest.uniprot.org/uniprotkb/Q4LE39.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q4LE39/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4LE39"}},"corpus_meta":[{"pmid":"28514443","id":"PMC_28514443","title":"Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514443","citation_count":329,"is_preprint":false},{"pmid":"20093359","id":"PMC_20093359","title":"Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20093359","citation_count":315,"is_preprint":false},{"pmid":"29779826","id":"PMC_29779826","title":"The BCKDH Kinase and Phosphatase Integrate BCAA and Lipid Metabolism via Regulation of ATP-Citrate Lyase.","date":"2018","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29779826","citation_count":282,"is_preprint":false},{"pmid":"31167878","id":"PMC_31167878","title":"Targeting BCAA Catabolism to Treat Obesity-Associated Insulin 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Hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/15607141","citation_count":13,"is_preprint":false},{"pmid":"33708192","id":"PMC_33708192","title":"Gentamicin Induced Microbiome Adaptations Associate With Increased BCAA Levels and Enhance Severity of Influenza Infection.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33708192","citation_count":13,"is_preprint":false},{"pmid":"32007808","id":"PMC_32007808","title":"A high-protein diet, not isolated BCAA, is associated with skeletal muscle mass index in patients with gastrointestinal cancer.","date":"2019","source":"Nutrition (Burbank, Los Angeles County, Calif.)","url":"https://pubmed.ncbi.nlm.nih.gov/32007808","citation_count":13,"is_preprint":false},{"pmid":"21584761","id":"PMC_21584761","title":"Changes in transcription during recovery from heat injury in Salmonella typhimurium and effects of BCAA on recovery.","date":"2011","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/21584761","citation_count":13,"is_preprint":false},{"pmid":"36518669","id":"PMC_36518669","title":"Evaluation of therapeutic strategies targeting BCAA catabolism using a systems pharmacology model.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36518669","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52149,"output_tokens":3927,"usd":0.107676},"stage2":{"model":"claude-opus-4-6","input_tokens":7315,"output_tokens":3367,"usd":0.181125},"total_usd":0.288801,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"RBBP1/ARID4A interacts physically with RBBP1L1/ARID4B and with the Snrpn promoter, and combined deficiency of Arid4a and Arid4b alters epigenetic modifications (reduced trimethylation of H4K20 and H3K9, reduced DNA methylation) at the PWS-IC, changing the maternal allele toward a more paternal epigenotype; mutations in Arid4a, Arid4b, or Rb suppressed an Angelman syndrome imprinting defect caused by a mutation at the AS-IC.\",\n      \"method\": \"Gene trap mutagenesis, gene knockout mice, western blotting, immunofluorescence, co-immunoprecipitation/promoter interaction assays, genetic epistasis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetics, epistasis, biochemical interaction, chromatin modification assays) in a single rigorous study\",\n      \"pmids\": [\"17043311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Arid4a-deficient mice progressed from ineffective hematopoiesis to CMML-like myeloproliferative disorder to AML; haploinsufficiency of Arid4b dramatically accelerated AML development (10/12 double-mutant mice vs 5/42 Arid4a-/- alone). Loss of Arid4a increased histone trimethylation of H3K4, H3K9, and H4K20 in bone marrow, and decreased expression of Hox genes (Hoxb3, b5, b6, b8) and FoxP3.\",\n      \"method\": \"Mouse knockout/haploinsufficiency models, complete blood counts, flow cytometry, histology, RT-PCR, western blotting, immunofluorescence\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/haploinsufficiency with defined leukemic phenotype plus molecular mechanism (histone methylation changes, downstream gene expression), replicated across two genotypes\",\n      \"pmids\": [\"18728284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ARID4B physically interacts with breast cancer metastasis suppressor BRMS1 and with histone deacetylase complex members mSIN3A and mSDS3; allelic variants of Arid4b show differential binding to these HDAC complex members. Ectopic Arid4b expression promoted primary tumor growth and increased cell migration/invasion, while shRNA-mediated knockdown reduced pulmonary metastases and downregulated the Tpx2 gene network regulating cell cycle and mitotic spindle biology.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown in vivo (mouse MMTV-PyMT model), ectopic overexpression, in vitro migration/invasion assays, gene expression profiling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP for protein interactions, combined with in vivo KD showing defined metastatic phenotype and gene network changes\",\n      \"pmids\": [\"22693453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ARID4A and ARID4B physically interact with each other; ARID4A is a retinoblastoma (RB)-binding protein. In Sertoli cells, ARID4A and ARID4B function as transcriptional coactivators for androgen receptor (AR) and RB, regulating downstream AR- and RB-responsive genes. Combined deficiency causes spermatogenic arrest, impaired blood-testis barrier, and seminal vesicle agenesis/hypodysplasia, phenocopying Sertoli cell-specific AR and RB knockouts.\",\n      \"method\": \"Mouse knockout/haploinsufficiency models, physical interaction assays (co-IP), gene expression analysis of AR/RB downstream targets, histology, blood-testis barrier permeability assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction demonstrated, combined with genetic epistasis (phenocopy of AR/RB knockouts) and downstream target analysis\",\n      \"pmids\": [\"23487765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"miR-290-3p directly targets the 3' UTR of Arid4b mRNA (confirmed by luciferase reporter assay), suppressing ARID4B expression and thereby suppressing breast cancer progression; miR-290 upregulation also elevated estrogen receptor levels, increasing apoptosis.\",\n      \"method\": \"miRNA microarray, luciferase reporter assay, in vivo tumor/metastasis models, pathway analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase reporter validates direct miR-290-3p targeting of ARID4B 3'UTR; single lab\",\n      \"pmids\": [\"23447578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ARID4B functions as a coactivator of androgen receptor (AR) in Sertoli cells and is required for optimal transcriptional activation of reproductive homeobox 5 (Rhox5), an AR target gene. Sertoli cell-specific Arid4b knockout mice are completely infertile with Sertoli cell-only phenotype, germ cell loss, and spermatogenic arrest at the round spermatid stage; Sertoli cell maturation is delayed.\",\n      \"method\": \"Sertoli cell-specific conditional knockout mice, histology, immunofluorescence, gene expression analysis, AR coactivation assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with defined phenotype plus mechanistic coactivator function demonstrated for AR/Rhox5\",\n      \"pmids\": [\"26258622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Sertoli cell-specific Arid4b knockout testes, ARID4B ablation causes abnormal Sertoli cell detachment from the basement membrane during the gonocyte-to-SSC transition, failure to establish the stem cell niche, gonocyte apoptosis, and impaired SSC self-renewal. ARID4B regulates downstream niche genes including gap junction protein alpha-1, KIT ligand, AMH, GDNF, inhibin alpha/beta, and Cyp26b1.\",\n      \"method\": \"Sertoli cell-specific conditional knockout mice, gene expression profiling, histology, cell fate analysis\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined cellular phenotype (niche failure) plus identification of downstream effector network\",\n      \"pmids\": [\"28207192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTEN inhibits expression of ARID4B; ARID4B acts as a transcriptional activator of PI3K subunit genes PIK3CA and PIK3R2 by binding their promoters; reciprocal binding of ARID4B and histone H1 to PIK3CA and PIK3R2 promoters modulates chromatin condensation. ARID4B is required for prostate tumorigenesis specifically when PTEN is deficient, defining a PTEN-ARID4B-PI3K axis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter binding assays, loss-of-function experiments, gene expression analysis, in vivo tumorigenesis models, patient data analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP validates direct promoter binding, epistasis established by PTEN-deficiency dependence, multiple orthogonal methods\",\n      \"pmids\": [\"31551414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARID4B is critical for mouse embryonic stem cell differentiation toward mesodermal and endodermal lineages. Arid4b-deficient mESCs self-renew normally but fail to upregulate meso/endodermal gene expression programs. ARID4B physically and functionally interacts with HDAC1 (but not HDAC2) within the SIN3A complex. ARID4B deficiency leads to increased H3K27me3 and reduced H3K27Ac at key developmental gene loci, while a subset of regions gain H3K27Ac.\",\n      \"method\": \"Pooled epigenetic shRNA screen, conditional knockout mESCs, differentiation assays, co-immunoprecipitation, ChIP-seq for H3K27me3/H3K27Ac, gene expression profiling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — functional screen, KO differentiation phenotype, physical interaction with HDAC1, chromatin modification mapping via ChIP-seq, multiple orthogonal methods\",\n      \"pmids\": [\"33454011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-30d directly regulates ARID4B (and ARID4A) expression in prostate cancer; mRNA expression of miR-30d is significantly negatively correlated with ARID4B. Knockout of ARID4B promoted prostate cancer cell proliferation, migration, and invasion in vitro, supporting a tumor suppressor function.\",\n      \"method\": \"miRNA-mRNA correlation in patient tissues, in vitro knockout, proliferation/migration/invasion assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — correlation-based miRNA targeting without direct luciferase validation; functional KO data supports tumor suppressor role\",\n      \"pmids\": [\"29797600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-519b-3p directly binds the 3' UTR of ARID4B mRNA and negatively regulates its expression; overexpression of miR-519b-3p enhanced responsiveness to chemoradiation in rectal cancer cells in an ARID4B-dependent manner.\",\n      \"method\": \"Luciferase reporter assay, overexpression/knockdown in vitro, patient tissue correlation\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — luciferase reporter confirms direct 3'UTR targeting; functional rescue confirms ARID4B dependence; single lab\",\n      \"pmids\": [\"29477868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Circ-SMARCA5 functions as a tumor suppressor in colorectal cancer by sponging miR-93-3p (predicted as miR-39-3p in abstract), thereby upregulating ARID4B expression; this axis inhibits CRC cell proliferation, migration, and invasion in vitro and tumor progression in vivo.\",\n      \"method\": \"qRT-PCR, luciferase reporter assay, overexpression, CCK-8/wound healing/Transwell assays, xenograft model\",\n      \"journal\": \"Digestive and liver disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase reporter validates miRNA-ARID4B interaction; functional rescue confirms pathway; single lab\",\n      \"pmids\": [\"32807692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARID4B knockdown in human glioma cells suppressed PI3K/AKT/mTOR pathway components (p-mTOR, p-PI3K, p-AKT), caused G1 phase arrest by downregulating Cyclin D1, increased HDAC1 expression leading to elevated acetyl-p53 and acetyl-H3 levels, and induced apoptosis; it also reduced glioma cell migration and invasion.\",\n      \"method\": \"Lentiviral shRNA knockdown, western blotting, flow cytometry (cell cycle/apoptosis), proliferation assay, migration/invasion assay\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD with defined signaling phenotype but pathway placement inferred from downstream markers without reconstitution\",\n      \"pmids\": [\"33732001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Taurine promotes protein synthesis and proliferation of C2C12 myoblast cells through the PI3K-ARID4B-mTOR pathway; ARID4B expression is induced by taurine in a PI3K-dependent manner. ARID4B binds to the -4368 to -4591 bp site of the mTOR promoter (confirmed by ChIP-PCR), promoting H3K27ac (but not H3K27me3) at this site, and ARID4B knockdown abolishes taurine-stimulated mTOR expression and mTOR phosphorylation.\",\n      \"method\": \"siRNA knockdown, CRISPR/dCas9 gene activation, ChIP-PCR and ChIP-qPCR, PI3K inhibitor (LY294002), western blotting, proliferation assay\",\n      \"journal\": \"The British journal of nutrition\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct promoter binding; ARID4B KD/activation epistasis places it in PI3K→ARID4B→mTOR axis; single lab\",\n      \"pmids\": [\"34881695\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARID4B is a chromatin-associated protein that physically interacts with ARID4A/RB and operates within the SIN3A-HDAC1 complex to regulate histone modifications (H3K27ac, H3K27me3, H3K4me3, H3K9me3, H4K20me3) at developmental and oncogenic loci; it acts as a transcriptional coactivator for androgen receptor (AR) and RB in Sertoli cells (driving spermatogenesis and niche establishment), directly binds and activates the PIK3CA/PIK3R2 promoters to sustain PI3K/AKT signaling downstream of PTEN loss in prostate cancer, and is required for mesoderm/endoderm differentiation of embryonic stem cells, while being post-transcriptionally regulated by multiple miRNAs (miR-290-3p, miR-30d, miR-519b-3p) that target its 3'UTR.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ARID4B is a chromatin-regulatory protein that operates within the SIN3A–HDAC1 complex to modulate histone modifications—including H3K27ac, H3K27me3, H3K4me3, H3K9me3, and H4K20me3—at developmental, imprinted, and oncogenic loci, thereby controlling transcriptional programs required for embryonic stem cell differentiation toward mesoderm/endoderm lineages, genomic imprinting at the PWS/AS locus, and hematopoietic homeostasis [PMID:33454011, PMID:17043311, PMID:18728284]. ARID4B physically interacts with ARID4A and RB and functions as a transcriptional coactivator for androgen receptor in Sertoli cells, where it is essential for spermatogenesis, blood–testis barrier integrity, and establishment of the spermatogonial stem cell niche [PMID:23487765, PMID:26258622, PMID:28207192]. In PTEN-deficient prostate cancer, ARID4B directly binds the PIK3CA and PIK3R2 promoters to sustain PI3K/AKT signaling, and it similarly activates the mTOR promoter by promoting H3K27 acetylation, establishing ARID4B as a chromatin-dependent transcriptional activator of the PI3K–AKT–mTOR axis [PMID:31551414, PMID:34881695]. Arid4b haploinsufficiency cooperates with Arid4a loss to accelerate acute myeloid leukemia in mice, and its expression is post-transcriptionally regulated by multiple miRNAs including miR-290-3p and miR-519b-3p [PMID:18728284, PMID:23447578, PMID:29477868].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"The question of whether ARID4B participates in epigenetic regulation of genomic imprinting was answered: combined Arid4a/Arid4b deficiency altered histone methylation and DNA methylation at the PWS imprinting center, establishing both proteins as chromatin regulators of imprinted loci acting through RB.\",\n      \"evidence\": \"Gene-trap and knockout mice with co-IP, chromatin modification assays, and genetic epistasis with AS-IC mutation\",\n      \"pmids\": [\"17043311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID4B directly binds the PWS-IC or acts indirectly through RB\", \"Structural basis of ARID4A–ARID4B interaction\", \"Whether ARID4B has independent functions at imprinted loci apart from ARID4A\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Whether ARID4B cooperates with ARID4A in tumor suppression was resolved: Arid4b haploinsufficiency dramatically accelerated the progression from myeloproliferative disorder to AML in Arid4a-null mice, linking both proteins to hematopoietic homeostasis via histone methylation of Hox gene loci.\",\n      \"evidence\": \"Mouse knockout/haploinsufficiency models with histology, flow cytometry, and histone mark analysis in bone marrow\",\n      \"pmids\": [\"18728284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID4B loss alone is sufficient for leukemogenesis\", \"Direct genomic targets of ARID4B in hematopoietic progenitors\", \"Mechanism by which histone trimethylation changes regulate Hox gene expression\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The molecular complex context of ARID4B was clarified: ARID4B physically interacts with BRMS1, mSIN3A, and mSDS3, placing it in the SIN3A–HDAC complex, and its expression promotes breast cancer metastasis through the Tpx2 gene network.\",\n      \"evidence\": \"Reciprocal co-IP for protein interactions, shRNA knockdown in MMTV-PyMT mouse model, gene expression profiling\",\n      \"pmids\": [\"22693453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID4B directly regulates Tpx2 transcription or acts indirectly\", \"Allelic variant effects on HDAC complex stoichiometry in vivo\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"ARID4B was established as a transcriptional coactivator for androgen receptor and RB in Sertoli cells: combined Arid4a/Arid4b deficiency phenocopied AR and RB knockouts, causing spermatogenic arrest and blood–testis barrier defects.\",\n      \"evidence\": \"Mouse knockout models, co-IP, AR/RB target gene expression analysis, histology and barrier permeability assays\",\n      \"pmids\": [\"23487765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID4B coactivator function depends on its ARID domain DNA binding\", \"Whether ARID4B acts as coactivator in tissues other than Sertoli cells\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Post-transcriptional regulation of ARID4B was demonstrated: miR-290-3p directly targets the ARID4B 3'UTR, suppressing its expression and thereby inhibiting breast cancer progression.\",\n      \"evidence\": \"Luciferase reporter assay for direct 3'UTR targeting, in vivo tumor/metastasis models\",\n      \"pmids\": [\"23447578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts in which miR-290-3p regulates ARID4B beyond breast cancer\", \"Quantitative contribution of miR-290-3p versus other miRNAs to ARID4B regulation\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The cell-autonomous requirement for ARID4B in male fertility was defined: Sertoli cell-specific Arid4b knockout caused complete infertility with spermatogenic arrest, confirming ARID4B as essential for AR coactivation of Rhox5 and Sertoli cell maturation.\",\n      \"evidence\": \"Sertoli cell-specific conditional knockout mice, histology, AR coactivation assay\",\n      \"pmids\": [\"26258622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID4B binds Rhox5 regulatory regions directly\", \"Genome-wide AR-dependent targets requiring ARID4B coactivation in Sertoli cells\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"ARID4B's role was extended from spermatogenesis to stem cell niche establishment: its loss in Sertoli cells caused failure to establish the spermatogonial stem cell niche, with defective expression of niche factors (GDNF, KIT ligand, gap junction proteins).\",\n      \"evidence\": \"Sertoli cell-specific conditional knockout, gene expression profiling, cell fate analysis\",\n      \"pmids\": [\"28207192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID4B directly binds niche gene promoters or acts through intermediate regulators\", \"Whether ARID4B regulates stem cell niches in other tissues\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Additional miRNA regulators of ARID4B were identified: miR-519b-3p directly binds ARID4B 3'UTR to modulate chemoradiation sensitivity in rectal cancer, and miR-30d expression negatively correlates with ARID4B in prostate cancer.\",\n      \"evidence\": \"Luciferase reporter assays (miR-519b-3p), miRNA-mRNA correlation and functional knockout (miR-30d)\",\n      \"pmids\": [\"29477868\", \"29797600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"miR-30d targeting of ARID4B lacks direct luciferase validation\", \"Relative contribution of different miRNAs to ARID4B protein levels in individual cancer types\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The mechanism by which ARID4B sustains PI3K/AKT signaling in PTEN-deficient tumors was resolved: ARID4B directly binds PIK3CA and PIK3R2 promoters, competing with histone H1 to maintain open chromatin, and is specifically required for prostate tumorigenesis when PTEN is lost.\",\n      \"evidence\": \"ChIP for direct promoter binding, loss-of-function epistasis with PTEN, in vivo tumorigenesis models, patient data\",\n      \"pmids\": [\"31551414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID4B–histone H1 competition is a general mechanism at other ARID4B targets\", \"Structural basis for ARID4B promoter recognition at PIK3CA/PIK3R2\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ARID4B's role in pluripotent cell differentiation was established: it is required for mesoderm/endoderm lineage commitment of mESCs, physically and functionally interacts with HDAC1 (not HDAC2) within SIN3A, and its loss causes redistribution of H3K27me3/H3K27ac at developmental loci.\",\n      \"evidence\": \"Pooled epigenetic shRNA screen, conditional knockout mESCs, co-IP, ChIP-seq for H3K27me3/H3K27ac\",\n      \"pmids\": [\"33454011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why ARID4B selectively interacts with HDAC1 but not HDAC2\", \"How ARID4B loss both increases and decreases H3K27ac at different loci\", \"Identity of direct ARID4B-bound genomic sites genome-wide\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ARID4B was shown to directly activate the mTOR promoter by promoting H3K27ac at a specific upstream site, placing it as a chromatin effector in the PI3K→ARID4B→mTOR signaling axis in myoblasts.\",\n      \"evidence\": \"ChIP-PCR/ChIP-qPCR for mTOR promoter binding, siRNA knockdown and dCas9 activation epistasis, PI3K inhibitor treatment\",\n      \"pmids\": [\"34881695\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ARID4B-mediated mTOR promoter activation operates in cell types beyond myoblasts\", \"Whether HDAC1/SIN3A complex is involved at the mTOR promoter\", \"Mechanism by which PI3K activity induces ARID4B expression\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A genome-wide map of direct ARID4B binding sites, the structural basis for its ARID domain specificity, and whether its coactivator versus repressor functions are context-dependent or reflect distinct complex compositions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No genome-wide ARID4B ChIP-seq in any cell type\", \"No structural model of ARID4B or its ARID domain bound to DNA\", \"Mechanism determining whether ARID4B promotes or removes H3K27ac at specific loci\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 5, 7, 8, 13]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 8, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 8]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 8, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 12, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 7]}\n    ],\n    \"complexes\": [\n      \"SIN3A-HDAC1 complex\"\n    ],\n    \"partners\": [\n      \"ARID4A\",\n      \"RB1\",\n      \"HDAC1\",\n      \"SIN3A\",\n      \"BRMS1\",\n      \"AR\",\n      \"SDS3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}