{"gene":"ARID4B","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2001,"finding":"RBP1L1/ARID4B encodes a 1226-amino acid protein sharing 37% amino acid identity with retinoblastoma-binding protein 1 (RBP1/ARID4A); the protein localizes to the cytoplasm of MCF-7 breast cancer cells, as determined by immunoperoxidase staining with purified RBP1L1-specific IgG.","method":"cDNA library screening, Western blot, immunoperoxidase staining","journal":"Journal of the National Cancer Institute","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, protein characterization by immunostaining and sequence analysis, two methods but no functional mechanistic follow-up","pmids":["11481388"],"is_preprint":false},{"year":2004,"finding":"BRCAA1/ARID4B protein contains a novel antigen epitope (SSKKQKRSHK) at residues 610–619 and localizes to the cytoplasm of MCF-7 cells; the protein shares 37% identity with RBP1 and 74% with a partial RBP1 sequence, and its expression is associated with ER/PR status in breast cancer.","method":"Peptide synthesis, competitive inhibition ELISA, immunohistochemistry, Western blot","journal":"Cancer epidemiology, biomarkers & prevention","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, cytoplasmic localization confirmed by IHC and ELISA with synthesized epitope peptide","pmids":["15247124"],"is_preprint":false},{"year":2006,"finding":"ARID4B (Rbbp1l1/Arid4b) physically interacts with ARID4A (Rbbp1/Arid4a) and with the Snrpn promoter, forming part of an epigenetic complex. Combined homozygous deficiency of Arid4a and heterozygous deficiency of Arid4b in mice 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 Arid4b (or Arid4a, or Rb) suppressed an Angelman syndrome imprinting defect caused by a mutation at the AS-IC.","method":"Gene trap mutagenesis, co-immunoprecipitation (inferred from protein complex membership), chromatin immunoprecipitation, mouse knockout genetics, Western blot for histone modifications, bisulfite sequencing","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic epistasis, histone modification analysis, promoter binding, mouse KO), replicated across allele combinations in a single rigorous study","pmids":["17043311"],"is_preprint":false},{"year":2008,"finding":"Arid4b haploinsufficiency combined with Arid4a deficiency in mice accelerates progression to acute myeloid leukemia (AML); Arid4a/Arid4b deficiency decreases expression of Hox genes (Hoxb3, Hoxb5, Hoxb6, Hoxb8) and FoxP3 in bone marrow, and increases histone trimethylation of H3K4, H3K9, and H4K20, identifying Arid4a and Arid4b as leukemia suppressor genes that regulate hematopoietic gene expression through histone modification.","method":"Mouse knockout genetics, complete blood counts, flow cytometry, histology, RT-PCR, Western blot, immunofluorescence for histone modifications","journal":"Journal of the National Cancer Institute","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean mouse KO with defined leukemic phenotype, multiple orthogonal methods (flow cytometry, RT-PCR, histone modification analysis), single lab but comprehensive","pmids":["18728284"],"is_preprint":false},{"year":2012,"finding":"ARID4B physically interacts with the breast cancer metastasis suppressor BRMS1, and also differentially binds to histone deacetylase complex members mSIN3A and mSDS3 depending on allelic variant. Ectopic expression of Arid4b promotes primary tumor growth and increases migration and invasion in vitro; shRNA knockdown reduces pulmonary metastases. Downregulation of the Tpx2 gene network (cell cycle and mitotic spindle regulators) accompanies loss of metastatic efficiency in Arid4b knockdown cells.","method":"Co-immunoprecipitation, shRNA knockdown, in vivo tumor/metastasis assays, in vitro migration/invasion assays, gene expression profiling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal protein interaction (Co-IP with BRMS1, mSIN3A, mSDS3), loss-of-function with defined metastatic phenotype in vivo and in vitro, multiple orthogonal methods","pmids":["22693453"],"is_preprint":false},{"year":2013,"finding":"ARID4A and ARID4B physically interact with each other; ARID4A is an RB-binding protein. In Arid4a−/−Arid4b+/− mice, combined deficiency causes progressive loss of male fertility with hypogonadism, spermatogenic arrest, and impaired blood-testis barrier integrity — phenotypes that recapitulate Sertoli cell-specific AR knockout and RB knockout mice. ARID4A and ARID4B were identified as transcriptional coactivators for androgen receptor (AR) and RB, with several AR- and RB-responsive genes identified as downstream targets.","method":"Co-immunoprecipitation (ARID4A–ARID4B interaction), mouse knockout genetics, histology, blood-testis barrier permeability assay, gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP for protein interaction, mouse KO with defined phenotype, genetic epistasis linking ARID4A/4B to AR and RB pathways, multiple methods","pmids":["23487765"],"is_preprint":false},{"year":2013,"finding":"miR-290-3p directly targets the 3' UTR of Arid4b mRNA, as confirmed by luciferase reporter assay; miR-290 upregulation suppresses both primary breast tumor growth and metastasis, and this effect is mediated through repression of Arid4b. Pathway analysis identified estrogen receptor (ER) signaling as a top canonical pathway affected by miR-290 upregulation.","method":"miRNA microarray, luciferase reporter assay, in vivo tumor/metastasis assays, pathway analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates direct miR-290-3p targeting of Arid4b 3'UTR, in vivo metastasis assay, single lab","pmids":["23447578"],"is_preprint":false},{"year":2015,"finding":"ARID4B is required in Sertoli cells for spermatogenesis; Sertoli cell-specific Arid4b knockout (Arid4bSCKO) mice are completely infertile, showing impaired testis development, loss of germ cells, Sertoli cell-only phenotype, and delayed Sertoli cell maturation with spermatogenic arrest at the round spermatid stage. ARID4B functions as a coactivator of the androgen receptor (AR) and is required for optimal transcriptional activation of reproductive homeobox 5 (Rhox5), an AR target gene in Sertoli cells.","method":"Sertoli cell-specific Cre-lox knockout, histology, fertility testing, RT-PCR/gene expression analysis, androgen receptor coactivation assay","journal":"Molecular endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined infertility phenotype, mechanistic link to AR coactivation and specific target gene (Rhox5) identified, multiple orthogonal methods","pmids":["26258622"],"is_preprint":false},{"year":2017,"finding":"In Sertoli cell-specific Arid4b knockout mice, ARID4B ablation causes abnormal detachment of Sertoli cells from the basement membrane during the gonocyte-to-SSC transition, preventing niche establishment for spermatogonial stem cell (SSC) formation. Gene expression profiling identified downstream effectors of ARID4B including gap junction protein alpha-1, KIT ligand, anti-Müllerian hormone, GDNF, inhibin alpha/beta, and CYP26B1 as genes governing SSC niche function.","method":"Sertoli cell-specific Arid4b knockout, histology, gene expression profiling, gonocyte distribution and apoptosis analysis","journal":"Stem cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with defined niche phenotype, transcriptomic identification of downstream effectors, multiple orthogonal methods in one study","pmids":["28207192"],"is_preprint":false},{"year":2018,"finding":"miR-519b-3p directly binds the 3' UTR of ARID4B mRNA (validated by luciferase assay), and miR-519b-3p overexpression enhances responsiveness to chemoradiation in rectal cancer cells in an ARID4B-dependent manner.","method":"Luciferase reporter assay, miRNA overexpression, in vitro chemoradiation response assays","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase reporter validates direct miRNA-3'UTR interaction, functional rescue experiment links effect to ARID4B, single lab","pmids":["29477868"],"is_preprint":false},{"year":2019,"finding":"PTEN suppresses ARID4B expression, while ARID4B acts as a transcriptional activator of PI3K subunit genes PIK3CA and PIK3R2, which are crucial for PI3K/AKT pathway activation. Reciprocal binding of ARID4B and histone H1 to the PIK3CA and PIK3R2 promoters modulates chromatin condensation. ARID4B is required for prostate tumorigenesis when PTEN is deficient, establishing a PTEN-ARID4B-PI3K axis.","method":"Chromatin immunoprecipitation (ChIP), promoter binding assays, gene knockdown/overexpression, in vitro and in vivo tumorigenesis assays, patient gene signature analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP validates direct ARID4B binding to PIK3CA/PIK3R2 promoters, histone H1 competition defined, PTEN epistasis established, multiple orthogonal methods, single lab","pmids":["31551414"],"is_preprint":false},{"year":2020,"finding":"ARID4B is critical for mouse embryonic stem cell (mESC) differentiation toward mesodermal and endodermal lineages; Arid4b-deficient mESCs have normal pluripotency but fail to upregulate meso/endodermal gene expression programs. ARID4B physically and functionally interacts with HDAC1 (but not HDAC2) within the SIN3A complex, suggesting functionally distinct SIN3A subcomplexes. ARID4B deficiency leads to increased H3K27me3 and reduced H3K27Ac at key developmental gene loci.","method":"Pooled epigenetic shRNA screen, co-immunoprecipitation (ARID4B–HDAC1 interaction), mESC differentiation assays, ChIP-seq for H3K27me3 and H3K27Ac, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP validates ARID4B–HDAC1 interaction, ChIP-seq defines histone modification changes, functional differentiation assays, multiple orthogonal methods in one study","pmids":["33454011"],"is_preprint":false},{"year":2020,"finding":"Circ-SMARCA5 sponges miR-93-3p (also described as miR-39-3p in the abstract), and ARID4B is a direct target of this miRNA; circ-SMARCA5 upregulates ARID4B expression by sponging the miRNA, thereby inhibiting colorectal cancer cell proliferation, migration, and invasion. The miRNA–ARID4B interaction was validated by luciferase reporter assay.","method":"qRT-PCR, luciferase reporter assay, CCK-8 proliferation assay, wound healing assay, Transwell invasion assay, xenograft model","journal":"Digestive and liver disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase assay validates miRNA targeting of ARID4B 3'UTR but the paper primarily focuses on the circular RNA; the abstract has inconsistent miRNA naming (miR-93-3p vs miR-39-3p)","pmids":["32807692"],"is_preprint":false},{"year":2021,"finding":"ARID4B knockdown in human glioma cells suppresses PI3K/AKT signaling (decreased p-mTOR, p-PI3K, p-AKT), induces G1 phase arrest via downregulation of Cyclin D1, increases HDAC1 expression leading to elevated acetyl-p53 and acetyl-H3, and reduces cell migration and invasion.","method":"shRNA knockdown via lentivirus, Western blot, flow cytometry (cell cycle), proliferation assay, migration/invasion assay","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — clean shRNA KD with defined signaling readouts, multiple phenotypic assays, single lab","pmids":["33732001"],"is_preprint":false},{"year":2021,"finding":"Taurine promotes ARID4B expression in a PI3K-dependent manner in C2C12 myoblasts. ARID4B directly binds the mTOR gene promoter (at the −4368 to −4591 bp site), and this binding is associated with H3K27ac (but not H3K27me3) at that site. ARID4B knockdown abolishes taurine-stimulated mTOR expression and phosphorylation, cell proliferation, and protein synthesis, whereas ARID4B gene activation (CRISPR/dCas9) has stimulatory effects, establishing a PI3K–ARID4B–mTOR pathway in muscle cells.","method":"ChIP-PCR, ChIP-qPCR, siRNA knockdown, CRISPR/dCas9 gene activation, Western blot, cell proliferation assay","journal":"The British journal of nutrition","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-PCR/qPCR directly identifies ARID4B binding to mTOR promoter with histone mark specificity, loss- and gain-of-function experiments with defined molecular readouts, multiple orthogonal methods","pmids":["34881695"],"is_preprint":false},{"year":2018,"finding":"ARID4B expression correlates with WHO grade in gliomas and meningiomas; in vitro ARID4B protein is elevated in some glioma cell lines relative to normal brain tissue (Western blot), establishing overexpression as a feature of malignant primary brain tumors.","method":"Western blot (cell lines), immunohistochemistry (tissue microarray), GEO dataset analysis","journal":"Journal of clinical pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression/IHC data only, no direct functional mechanistic experiment","pmids":["27451434"],"is_preprint":false}],"current_model":"ARID4B is a chromatin-associated protein that physically interacts with ARID4A, HDAC1 within the SIN3A complex, the retinoblastoma protein (RB), and the androgen receptor (AR), acting as a transcriptional coactivator and epigenetic regulator: it binds directly to gene promoters (including PIK3CA, PIK3R2, and mTOR) to modulate H3K27 acetylation and chromatin condensation, thereby activating the PI3K/AKT/mTOR pathway; its loss alters H3K4/H3K9/H4K20 trimethylation and impairs imprinting at the PWS/AS domain, and Sertoli-cell-specific deletion causes male infertility by disrupting AR-dependent gene programs and spermatogonial stem cell niche establishment."},"narrative":{"mechanistic_narrative":"ARID4B is a chromatin-associated transcriptional regulator that operates within histone-modifying complexes to control developmental, reproductive, and oncogenic gene programs [PMID:17043311, PMID:33454011]. It physically partners with its paralog ARID4A and, together with that protein, functions in epigenetic complexes that maintain repressive histone trimethylation (H3K9, H4K20) and DNA methylation at imprinted loci such as the PWS/AS domain, where combined Arid4a/Arid4b deficiency shifts the maternal allele toward a paternal epigenotype [PMID:17043311]. Within the SIN3A complex, ARID4B interacts specifically with HDAC1 (and not HDAC2) and with the corepressor components mSIN3A/mSDS3, and its activity governs the balance of H3K27 acetylation versus H3K27 trimethylation at developmental gene loci, where it is required for embryonic stem cell differentiation toward mesoderm and endoderm [PMID:33454011, PMID:22693453]. ARID4A and ARID4B act as transcriptional coactivators for the androgen receptor (AR) and the retinoblastoma protein (RB); in Sertoli cells, ARID4B is required for AR-dependent activation of target genes including Rhox5, and its loss causes complete male infertility with spermatogenic arrest, blood-testis barrier defects, and failure of spermatogonial stem cell niche establishment through dysregulation of effectors such as GDNF, KIT ligand, and CYP26B1 [PMID:23487765, PMID:26258622, PMID:28207192]. In cancer, ARID4B binds directly to the promoters of PI3K pathway genes — PIK3CA, PIK3R2, and mTOR — where it competes with histone H1 to modulate chromatin condensation and deposits activating H3K27ac, thereby driving PI3K/AKT/mTOR signaling; this places ARID4B downstream of PTEN as a required factor for prostate tumorigenesis and as a context-dependent regulator of tumor growth and metastasis [PMID:31551414, PMID:34881695, PMID:22693453]. ARID4B expression is post-transcriptionally constrained by multiple microRNAs targeting its 3'UTR [PMID:23447578, PMID:29477868].","teleology":[{"year":2001,"claim":"Established ARID4B as a distinct gene product related to but separate from the retinoblastoma-binding protein RBP1/ARID4A, defining the molecular identity of the protein.","evidence":"cDNA library screening and immunoperoxidase staining in MCF-7 breast cancer cells","pmids":["11481388","15247124"],"confidence":"Medium","gaps":["Cytoplasmic localization reported by IHC conflicts with later chromatin/nuclear function; no functional mechanism defined","Sequence relationship to ARID4A asserted without functional consequence"]},{"year":2006,"claim":"Showed ARID4B physically partners with ARID4A in an epigenetic complex that maintains imprinting, answering whether the two paralogs act together at chromatin.","evidence":"Mouse gene-trap genetics, ChIP at the Snrpn promoter, histone modification Western blots, and bisulfite sequencing at the PWS-IC","pmids":["17043311"],"confidence":"High","gaps":["Direct ARID4B-ARID4A binding inferred from complex membership rather than demonstrated by reciprocal Co-IP in this study","Mechanism by which the complex directs H4K20/H3K9 methylation not resolved"]},{"year":2008,"claim":"Defined ARID4A/ARID4B as leukemia suppressors that control hematopoietic gene expression through histone trimethylation, extending their epigenetic role to disease.","evidence":"Mouse knockout genetics with AML phenotyping, flow cytometry, RT-PCR, and histone modification analysis","pmids":["18728284"],"confidence":"High","gaps":["Direct promoter binding at Hox/FoxP3 loci not shown","Whether increased H3K4/H3K9/H4K20me3 is cause or consequence of transformation unresolved"]},{"year":2012,"claim":"Identified ARID4B as a metastasis-promoting factor that interacts with BRMS1 and HDAC complex members, linking it to corepressor machinery and tumor progression.","evidence":"Co-IP with BRMS1/mSIN3A/mSDS3, shRNA knockdown, in vivo metastasis assays, and gene expression profiling of the Tpx2 network","pmids":["22693453"],"confidence":"High","gaps":["Allele-dependent differential binding to mSIN3A/mSDS3 mechanistically unexplained","Direct ARID4B regulation of Tpx2 network genes not demonstrated by ChIP"]},{"year":2013,"claim":"Established ARID4A/ARID4B as transcriptional coactivators for AR and RB and demonstrated their requirement for male fertility and blood-testis barrier integrity.","evidence":"Co-IP of ARID4A-ARID4B, compound mouse knockouts, BTB permeability assays, and gene expression analysis","pmids":["23487765"],"confidence":"High","gaps":["Direct coactivation mechanism at AR/RB target promoters not dissected here","Relative contributions of AR versus RB pathways to the testis phenotype not separated"]},{"year":2013,"claim":"Showed Arid4b is a direct microRNA target whose repression by miR-290-3p suppresses breast tumor growth and metastasis, defining post-transcriptional control of its oncogenic activity.","evidence":"Luciferase 3'UTR reporter assay, miRNA microarray, and in vivo tumor/metastasis assays","pmids":["23447578"],"confidence":"Medium","gaps":["Whether ER pathway effects are direct ARID4B targets or secondary not resolved","Single lab"]},{"year":2015,"claim":"Pinpointed ARID4B as an AR coactivator required cell-autonomously in Sertoli cells for spermatogenesis, identifying Rhox5 as a direct functional AR target.","evidence":"Sertoli cell-specific Cre-lox knockout, fertility testing, histology, and AR coactivation assays","pmids":["26258622"],"confidence":"High","gaps":["Chromatin recruitment mechanism of ARID4B to AR target genes not defined","Full repertoire of AR targets requiring ARID4B not mapped"]},{"year":2017,"claim":"Extended the Sertoli-cell role of ARID4B to spermatogonial stem cell niche establishment, identifying the downstream effector genes controlling that niche.","evidence":"Sertoli cell-specific knockout with gonocyte distribution/apoptosis analysis and transcriptomic profiling","pmids":["28207192"],"confidence":"High","gaps":["Direct vs indirect regulation of GDNF/KITL/AMH/CYP26B1 by ARID4B not established","Mechanism linking ARID4B loss to basement-membrane detachment unknown"]},{"year":2019,"claim":"Defined a PTEN-ARID4B-PI3K axis in which ARID4B directly activates PI3K subunit genes by competing with histone H1 at their promoters, placing ARID4B as a chromatin-level driver of PI3K/AKT signaling.","evidence":"ChIP at PIK3CA/PIK3R2 promoters, knockdown/overexpression, in vivo prostate tumorigenesis, and patient signature analysis","pmids":["31551414"],"confidence":"High","gaps":["Mechanism of PTEN-mediated suppression of ARID4B expression not detailed","How ARID4B displaces H1 to alter condensation not structurally defined"]},{"year":2020,"claim":"Showed ARID4B controls ESC differentiation through HDAC1-specific SIN3A subcomplexes that govern the H3K27ac/H3K27me3 balance at developmental loci.","evidence":"Pooled epigenetic shRNA screen, Co-IP of ARID4B-HDAC1, mESC differentiation assays, and ChIP-seq for H3K27me3/H3K27Ac","pmids":["33454011"],"confidence":"High","gaps":["Basis for HDAC1 versus HDAC2 selectivity within SIN3A not resolved","Whether ARID4B targets developmental loci directly or via complex recruitment unclear"]},{"year":2021,"claim":"Demonstrated ARID4B directly binds the mTOR promoter to deposit activating H3K27ac, completing a PI3K-ARID4B-mTOR signaling pathway in muscle cells responsive to taurine.","evidence":"ChIP-PCR/qPCR, siRNA knockdown, CRISPR/dCas9 activation, and Western blots in C2C12 myoblasts","pmids":["34881695"],"confidence":"High","gaps":["Coupling between upstream PI3K signaling and ARID4B promoter recruitment not defined","Generalizability of mTOR promoter regulation beyond myoblasts not tested"]},{"year":2021,"claim":"Linked ARID4B to PI3K/AKT signaling and cell-cycle/HDAC1 control in glioma, reinforcing its pro-tumorigenic signaling role in a second tumor type.","evidence":"shRNA knockdown in glioma cells with Western blot, cell-cycle flow cytometry, and migration/invasion assays","pmids":["33732001"],"confidence":"Medium","gaps":["Direct promoter targets in glioma not identified by ChIP","The increase in HDAC1 upon ARID4B knockdown is mechanistically unexplained"]},{"year":null,"claim":"How ARID4B is recruited to specific promoters and switches between coactivator (H3K27ac deposition, H1 displacement) and corepressor (SIN3A/HDAC1, H3K27me3) modes in a context-dependent manner remains unresolved.","evidence":"No timeline study reconstitutes ARID4B targeting specificity or the determinant of its activator/repressor switch","pmids":[],"confidence":"Medium","gaps":["No structural model of ARID4B-chromatin or ARID4B-complex interactions","Determinants of promoter selectivity unknown","Mechanism toggling activating vs repressive chromatin output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,7,10,14]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,10,14]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[10,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,10,11]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,10,14]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,3,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,7,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,13,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8,11]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5,7,8]}],"complexes":["SIN3A complex"],"partners":["ARID4A","HDAC1","BRMS1","SIN3A","SDS3","AR","RB1","H1"],"other_free_text":[]}},"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 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Hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/15607138","citation_count":15,"is_preprint":false},{"pmid":"34881695","id":"PMC_34881695","title":"Taurine stimulates protein synthesis and proliferation of C2C12 myoblast cells through the PI3K-ARID4B-mTOR pathway.","date":"2021","source":"The British journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/34881695","citation_count":14,"is_preprint":false},{"pmid":"15607141","id":"PMC_15607141","title":"Nocturnal energy and BCAA supplementation in patients with liver cirrhosis.","date":"2004","source":"Hepatology research : the official journal of the Japan Society of Hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/15607141","citation_count":14,"is_preprint":false},{"pmid":"36361016","id":"PMC_36361016","title":"Prepregnancy Protein Source and BCAA Intake Are Associated with Gestational Diabetes Mellitus in the CARDIA Study.","date":"2022","source":"International journal of environmental research and public health","url":"https://pubmed.ncbi.nlm.nih.gov/36361016","citation_count":13,"is_preprint":false},{"pmid":"28207192","id":"PMC_28207192","title":"Temporal-Spatial Establishment of Initial Niche for the Primary Spermatogonial Stem Cell Formation Is Determined by an ARID4B Regulatory Network.","date":"2017","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/28207192","citation_count":13,"is_preprint":false},{"pmid":"32217465","id":"PMC_32217465","title":"Moderate intake of BCAA-rich protein improves glucose homeostasis in high-fat-fed mice.","date":"2020","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32217465","citation_count":13,"is_preprint":false},{"pmid":"37216755","id":"PMC_37216755","title":"Loss of BCAA catabolism enhances Rab1A-mTORC1 signaling activity and promotes tumor proliferation in NSCLC.","date":"2023","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37216755","citation_count":13,"is_preprint":false},{"pmid":"26086773","id":"PMC_26086773","title":"Dexamethasone and BCAA Failed to Modulate Muscle Mass and mTOR Signaling in GH-Deficient Rats.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26086773","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":"37720080","id":"PMC_37720080","title":"Empowering frail older adults: multicomponent elastic-band exercises and BCAA supplementation unleash physical health and preserve haematological biomarkers.","date":"2023","source":"Frontiers in sports and active living","url":"https://pubmed.ncbi.nlm.nih.gov/37720080","citation_count":12,"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":53149,"output_tokens":5091,"usd":0.117906,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12729,"output_tokens":4398,"usd":0.086797,"stage2_stop_reason":"end_turn"},"total_usd":0.204703,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical ARID4B protein (also known as BCAA, BRCAA1, SAP180, RBP1L1).\n\n**Critical note on aliases:** The HGNC aliases for ARID4B include \"BCAA\" — but examining the corpus, papers 1-15, 17, 19-36, 38-48, 51-58, 60-62, 64-68, 71-78, 81, 83, 85-92, 94-100 are about branched-chain amino acid (BCAA) metabolism, not the ARID4B protein. \"BCAA\" as a gene symbol for ARID4B refers to the protein name alias, not branched-chain amino acids. I must not conflate the metabolite/pathway \"BCAA\" with the gene alias.\n\nPapers clearly about ARID4B protein: 16, 18, 27, 37, 41, 45, 47, 50, 63, 70, 76, 79, 80, 82, 84, 90, 93.\n\nPaper 38, 73: About BRCAA1 antibody for gastric cancer imaging — BRCAA1 is an alias for ARID4B, so these are relevant for localization/expression but minimally mechanistic.\n\nPaper 63: Characterizes BRCAA1 (=ARID4B) protein structure and antigen epitope — mechanistically relevant.\n\nNow extracting mechanistic findings:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"RBP1L1/ARID4B encodes a 1226-amino acid protein sharing 37% amino acid identity with retinoblastoma-binding protein 1 (RBP1/ARID4A); the protein localizes to the cytoplasm of MCF-7 breast cancer cells, as determined by immunoperoxidase staining with purified RBP1L1-specific IgG.\",\n      \"method\": \"cDNA library screening, Western blot, immunoperoxidase staining\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, protein characterization by immunostaining and sequence analysis, two methods but no functional mechanistic follow-up\",\n      \"pmids\": [\"11481388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BRCAA1/ARID4B protein contains a novel antigen epitope (SSKKQKRSHK) at residues 610–619 and localizes to the cytoplasm of MCF-7 cells; the protein shares 37% identity with RBP1 and 74% with a partial RBP1 sequence, and its expression is associated with ER/PR status in breast cancer.\",\n      \"method\": \"Peptide synthesis, competitive inhibition ELISA, immunohistochemistry, Western blot\",\n      \"journal\": \"Cancer epidemiology, biomarkers & prevention\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, cytoplasmic localization confirmed by IHC and ELISA with synthesized epitope peptide\",\n      \"pmids\": [\"15247124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ARID4B (Rbbp1l1/Arid4b) physically interacts with ARID4A (Rbbp1/Arid4a) and with the Snrpn promoter, forming part of an epigenetic complex. Combined homozygous deficiency of Arid4a and heterozygous deficiency of Arid4b in mice 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 Arid4b (or Arid4a, or Rb) suppressed an Angelman syndrome imprinting defect caused by a mutation at the AS-IC.\",\n      \"method\": \"Gene trap mutagenesis, co-immunoprecipitation (inferred from protein complex membership), chromatin immunoprecipitation, mouse knockout genetics, Western blot for histone modifications, bisulfite sequencing\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic epistasis, histone modification analysis, promoter binding, mouse KO), replicated across allele combinations in a single rigorous study\",\n      \"pmids\": [\"17043311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Arid4b haploinsufficiency combined with Arid4a deficiency in mice accelerates progression to acute myeloid leukemia (AML); Arid4a/Arid4b deficiency decreases expression of Hox genes (Hoxb3, Hoxb5, Hoxb6, Hoxb8) and FoxP3 in bone marrow, and increases histone trimethylation of H3K4, H3K9, and H4K20, identifying Arid4a and Arid4b as leukemia suppressor genes that regulate hematopoietic gene expression through histone modification.\",\n      \"method\": \"Mouse knockout genetics, complete blood counts, flow cytometry, histology, RT-PCR, Western blot, immunofluorescence for histone modifications\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean mouse KO with defined leukemic phenotype, multiple orthogonal methods (flow cytometry, RT-PCR, histone modification analysis), single lab but comprehensive\",\n      \"pmids\": [\"18728284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ARID4B physically interacts with the breast cancer metastasis suppressor BRMS1, and also differentially binds to histone deacetylase complex members mSIN3A and mSDS3 depending on allelic variant. Ectopic expression of Arid4b promotes primary tumor growth and increases migration and invasion in vitro; shRNA knockdown reduces pulmonary metastases. Downregulation of the Tpx2 gene network (cell cycle and mitotic spindle regulators) accompanies loss of metastatic efficiency in Arid4b knockdown cells.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, in vivo tumor/metastasis assays, in vitro migration/invasion assays, gene expression profiling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal protein interaction (Co-IP with BRMS1, mSIN3A, mSDS3), loss-of-function with defined metastatic phenotype in vivo and in vitro, multiple orthogonal methods\",\n      \"pmids\": [\"22693453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ARID4A and ARID4B physically interact with each other; ARID4A is an RB-binding protein. In Arid4a−/−Arid4b+/− mice, combined deficiency causes progressive loss of male fertility with hypogonadism, spermatogenic arrest, and impaired blood-testis barrier integrity — phenotypes that recapitulate Sertoli cell-specific AR knockout and RB knockout mice. ARID4A and ARID4B were identified as transcriptional coactivators for androgen receptor (AR) and RB, with several AR- and RB-responsive genes identified as downstream targets.\",\n      \"method\": \"Co-immunoprecipitation (ARID4A–ARID4B interaction), mouse knockout genetics, histology, blood-testis barrier permeability assay, gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP for protein interaction, mouse KO with defined phenotype, genetic epistasis linking ARID4A/4B to AR and RB pathways, multiple methods\",\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, as confirmed by luciferase reporter assay; miR-290 upregulation suppresses both primary breast tumor growth and metastasis, and this effect is mediated through repression of Arid4b. Pathway analysis identified estrogen receptor (ER) signaling as a top canonical pathway affected by miR-290 upregulation.\",\n      \"method\": \"miRNA microarray, luciferase reporter assay, in vivo tumor/metastasis assays, pathway analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates direct miR-290-3p targeting of Arid4b 3'UTR, in vivo metastasis assay, single lab\",\n      \"pmids\": [\"23447578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ARID4B is required in Sertoli cells for spermatogenesis; Sertoli cell-specific Arid4b knockout (Arid4bSCKO) mice are completely infertile, showing impaired testis development, loss of germ cells, Sertoli cell-only phenotype, and delayed Sertoli cell maturation with spermatogenic arrest at the round spermatid stage. ARID4B functions as a coactivator of the androgen receptor (AR) and is required for optimal transcriptional activation of reproductive homeobox 5 (Rhox5), an AR target gene in Sertoli cells.\",\n      \"method\": \"Sertoli cell-specific Cre-lox knockout, histology, fertility testing, RT-PCR/gene expression analysis, androgen receptor coactivation assay\",\n      \"journal\": \"Molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined infertility phenotype, mechanistic link to AR coactivation and specific target gene (Rhox5) identified, multiple orthogonal methods\",\n      \"pmids\": [\"26258622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Sertoli cell-specific Arid4b knockout mice, ARID4B ablation causes abnormal detachment of Sertoli cells from the basement membrane during the gonocyte-to-SSC transition, preventing niche establishment for spermatogonial stem cell (SSC) formation. Gene expression profiling identified downstream effectors of ARID4B including gap junction protein alpha-1, KIT ligand, anti-Müllerian hormone, GDNF, inhibin alpha/beta, and CYP26B1 as genes governing SSC niche function.\",\n      \"method\": \"Sertoli cell-specific Arid4b knockout, histology, gene expression profiling, gonocyte distribution and apoptosis analysis\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with defined niche phenotype, transcriptomic identification of downstream effectors, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28207192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-519b-3p directly binds the 3' UTR of ARID4B mRNA (validated by luciferase assay), and miR-519b-3p overexpression enhances responsiveness to chemoradiation in rectal cancer cells in an ARID4B-dependent manner.\",\n      \"method\": \"Luciferase reporter assay, miRNA overexpression, in vitro chemoradiation response assays\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase reporter validates direct miRNA-3'UTR interaction, functional rescue experiment links effect to ARID4B, single lab\",\n      \"pmids\": [\"29477868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTEN suppresses ARID4B expression, while ARID4B acts as a transcriptional activator of PI3K subunit genes PIK3CA and PIK3R2, which are crucial for PI3K/AKT pathway activation. Reciprocal binding of ARID4B and histone H1 to the PIK3CA and PIK3R2 promoters modulates chromatin condensation. ARID4B is required for prostate tumorigenesis when PTEN is deficient, establishing a PTEN-ARID4B-PI3K axis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter binding assays, gene knockdown/overexpression, in vitro and in vivo tumorigenesis assays, patient gene signature analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP validates direct ARID4B binding to PIK3CA/PIK3R2 promoters, histone H1 competition defined, PTEN epistasis established, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31551414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARID4B is critical for mouse embryonic stem cell (mESC) differentiation toward mesodermal and endodermal lineages; Arid4b-deficient mESCs have normal pluripotency but fail to upregulate meso/endodermal gene expression programs. ARID4B physically and functionally interacts with HDAC1 (but not HDAC2) within the SIN3A complex, suggesting functionally distinct SIN3A subcomplexes. ARID4B deficiency leads to increased H3K27me3 and reduced H3K27Ac at key developmental gene loci.\",\n      \"method\": \"Pooled epigenetic shRNA screen, co-immunoprecipitation (ARID4B–HDAC1 interaction), mESC differentiation assays, ChIP-seq for H3K27me3 and H3K27Ac, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP validates ARID4B–HDAC1 interaction, ChIP-seq defines histone modification changes, functional differentiation assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"33454011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Circ-SMARCA5 sponges miR-93-3p (also described as miR-39-3p in the abstract), and ARID4B is a direct target of this miRNA; circ-SMARCA5 upregulates ARID4B expression by sponging the miRNA, thereby inhibiting colorectal cancer cell proliferation, migration, and invasion. The miRNA–ARID4B interaction was validated by luciferase reporter assay.\",\n      \"method\": \"qRT-PCR, luciferase reporter assay, CCK-8 proliferation assay, wound healing assay, Transwell invasion assay, xenograft model\",\n      \"journal\": \"Digestive and liver disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase assay validates miRNA targeting of ARID4B 3'UTR but the paper primarily focuses on the circular RNA; the abstract has inconsistent miRNA naming (miR-93-3p vs miR-39-3p)\",\n      \"pmids\": [\"32807692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARID4B knockdown in human glioma cells suppresses PI3K/AKT signaling (decreased p-mTOR, p-PI3K, p-AKT), induces G1 phase arrest via downregulation of Cyclin D1, increases HDAC1 expression leading to elevated acetyl-p53 and acetyl-H3, and reduces cell migration and invasion.\",\n      \"method\": \"shRNA knockdown via lentivirus, Western blot, flow cytometry (cell cycle), proliferation assay, migration/invasion assay\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — clean shRNA KD with defined signaling readouts, multiple phenotypic assays, single lab\",\n      \"pmids\": [\"33732001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Taurine promotes ARID4B expression in a PI3K-dependent manner in C2C12 myoblasts. ARID4B directly binds the mTOR gene promoter (at the −4368 to −4591 bp site), and this binding is associated with H3K27ac (but not H3K27me3) at that site. ARID4B knockdown abolishes taurine-stimulated mTOR expression and phosphorylation, cell proliferation, and protein synthesis, whereas ARID4B gene activation (CRISPR/dCas9) has stimulatory effects, establishing a PI3K–ARID4B–mTOR pathway in muscle cells.\",\n      \"method\": \"ChIP-PCR, ChIP-qPCR, siRNA knockdown, CRISPR/dCas9 gene activation, Western blot, cell proliferation assay\",\n      \"journal\": \"The British journal of nutrition\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-PCR/qPCR directly identifies ARID4B binding to mTOR promoter with histone mark specificity, loss- and gain-of-function experiments with defined molecular readouts, multiple orthogonal methods\",\n      \"pmids\": [\"34881695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARID4B expression correlates with WHO grade in gliomas and meningiomas; in vitro ARID4B protein is elevated in some glioma cell lines relative to normal brain tissue (Western blot), establishing overexpression as a feature of malignant primary brain tumors.\",\n      \"method\": \"Western blot (cell lines), immunohistochemistry (tissue microarray), GEO dataset analysis\",\n      \"journal\": \"Journal of clinical pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression/IHC data only, no direct functional mechanistic experiment\",\n      \"pmids\": [\"27451434\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARID4B is a chromatin-associated protein that physically interacts with ARID4A, HDAC1 within the SIN3A complex, the retinoblastoma protein (RB), and the androgen receptor (AR), acting as a transcriptional coactivator and epigenetic regulator: it binds directly to gene promoters (including PIK3CA, PIK3R2, and mTOR) to modulate H3K27 acetylation and chromatin condensation, thereby activating the PI3K/AKT/mTOR pathway; its loss alters H3K4/H3K9/H4K20 trimethylation and impairs imprinting at the PWS/AS domain, and Sertoli-cell-specific deletion causes male infertility by disrupting AR-dependent gene programs and spermatogonial stem cell niche establishment.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARID4B is a chromatin-associated transcriptional regulator that operates within histone-modifying complexes to control developmental, reproductive, and oncogenic gene programs [#2, #11]. It physically partners with its paralog ARID4A and, together with that protein, functions in epigenetic complexes that maintain repressive histone trimethylation (H3K9, H4K20) and DNA methylation at imprinted loci such as the PWS/AS domain, where combined Arid4a/Arid4b deficiency shifts the maternal allele toward a paternal epigenotype [#2]. Within the SIN3A complex, ARID4B interacts specifically with HDAC1 (and not HDAC2) and with the corepressor components mSIN3A/mSDS3, and its activity governs the balance of H3K27 acetylation versus H3K27 trimethylation at developmental gene loci, where it is required for embryonic stem cell differentiation toward mesoderm and endoderm [#11, #4]. ARID4A and ARID4B act as transcriptional coactivators for the androgen receptor (AR) and the retinoblastoma protein (RB); in Sertoli cells, ARID4B is required for AR-dependent activation of target genes including Rhox5, and its loss causes complete male infertility with spermatogenic arrest, blood-testis barrier defects, and failure of spermatogonial stem cell niche establishment through dysregulation of effectors such as GDNF, KIT ligand, and CYP26B1 [#5, #7, #8]. In cancer, ARID4B binds directly to the promoters of PI3K pathway genes — PIK3CA, PIK3R2, and mTOR — where it competes with histone H1 to modulate chromatin condensation and deposits activating H3K27ac, thereby driving PI3K/AKT/mTOR signaling; this places ARID4B downstream of PTEN as a required factor for prostate tumorigenesis and as a context-dependent regulator of tumor growth and metastasis [#10, #14, #4]. ARID4B expression is post-transcriptionally constrained by multiple microRNAs targeting its 3'UTR [#6, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established ARID4B as a distinct gene product related to but separate from the retinoblastoma-binding protein RBP1/ARID4A, defining the molecular identity of the protein.\",\n      \"evidence\": \"cDNA library screening and immunoperoxidase staining in MCF-7 breast cancer cells\",\n      \"pmids\": [\"11481388\", \"15247124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cytoplasmic localization reported by IHC conflicts with later chromatin/nuclear function; no functional mechanism defined\", \"Sequence relationship to ARID4A asserted without functional consequence\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed ARID4B physically partners with ARID4A in an epigenetic complex that maintains imprinting, answering whether the two paralogs act together at chromatin.\",\n      \"evidence\": \"Mouse gene-trap genetics, ChIP at the Snrpn promoter, histone modification Western blots, and bisulfite sequencing at the PWS-IC\",\n      \"pmids\": [\"17043311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ARID4B-ARID4A binding inferred from complex membership rather than demonstrated by reciprocal Co-IP in this study\", \"Mechanism by which the complex directs H4K20/H3K9 methylation not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined ARID4A/ARID4B as leukemia suppressors that control hematopoietic gene expression through histone trimethylation, extending their epigenetic role to disease.\",\n      \"evidence\": \"Mouse knockout genetics with AML phenotyping, flow cytometry, RT-PCR, and histone modification analysis\",\n      \"pmids\": [\"18728284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct promoter binding at Hox/FoxP3 loci not shown\", \"Whether increased H3K4/H3K9/H4K20me3 is cause or consequence of transformation unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified ARID4B as a metastasis-promoting factor that interacts with BRMS1 and HDAC complex members, linking it to corepressor machinery and tumor progression.\",\n      \"evidence\": \"Co-IP with BRMS1/mSIN3A/mSDS3, shRNA knockdown, in vivo metastasis assays, and gene expression profiling of the Tpx2 network\",\n      \"pmids\": [\"22693453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Allele-dependent differential binding to mSIN3A/mSDS3 mechanistically unexplained\", \"Direct ARID4B regulation of Tpx2 network genes not demonstrated by ChIP\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established ARID4A/ARID4B as transcriptional coactivators for AR and RB and demonstrated their requirement for male fertility and blood-testis barrier integrity.\",\n      \"evidence\": \"Co-IP of ARID4A-ARID4B, compound mouse knockouts, BTB permeability assays, and gene expression analysis\",\n      \"pmids\": [\"23487765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct coactivation mechanism at AR/RB target promoters not dissected here\", \"Relative contributions of AR versus RB pathways to the testis phenotype not separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed Arid4b is a direct microRNA target whose repression by miR-290-3p suppresses breast tumor growth and metastasis, defining post-transcriptional control of its oncogenic activity.\",\n      \"evidence\": \"Luciferase 3'UTR reporter assay, miRNA microarray, and in vivo tumor/metastasis assays\",\n      \"pmids\": [\"23447578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ER pathway effects are direct ARID4B targets or secondary not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Pinpointed ARID4B as an AR coactivator required cell-autonomously in Sertoli cells for spermatogenesis, identifying Rhox5 as a direct functional AR target.\",\n      \"evidence\": \"Sertoli cell-specific Cre-lox knockout, fertility testing, histology, and AR coactivation assays\",\n      \"pmids\": [\"26258622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Chromatin recruitment mechanism of ARID4B to AR target genes not defined\", \"Full repertoire of AR targets requiring ARID4B not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended the Sertoli-cell role of ARID4B to spermatogonial stem cell niche establishment, identifying the downstream effector genes controlling that niche.\",\n      \"evidence\": \"Sertoli cell-specific knockout with gonocyte distribution/apoptosis analysis and transcriptomic profiling\",\n      \"pmids\": [\"28207192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect regulation of GDNF/KITL/AMH/CYP26B1 by ARID4B not established\", \"Mechanism linking ARID4B loss to basement-membrane detachment unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a PTEN-ARID4B-PI3K axis in which ARID4B directly activates PI3K subunit genes by competing with histone H1 at their promoters, placing ARID4B as a chromatin-level driver of PI3K/AKT signaling.\",\n      \"evidence\": \"ChIP at PIK3CA/PIK3R2 promoters, knockdown/overexpression, in vivo prostate tumorigenesis, and patient signature analysis\",\n      \"pmids\": [\"31551414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PTEN-mediated suppression of ARID4B expression not detailed\", \"How ARID4B displaces H1 to alter condensation not structurally defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed ARID4B controls ESC differentiation through HDAC1-specific SIN3A subcomplexes that govern the H3K27ac/H3K27me3 balance at developmental loci.\",\n      \"evidence\": \"Pooled epigenetic shRNA screen, Co-IP of ARID4B-HDAC1, mESC differentiation assays, and ChIP-seq for H3K27me3/H3K27Ac\",\n      \"pmids\": [\"33454011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis for HDAC1 versus HDAC2 selectivity within SIN3A not resolved\", \"Whether ARID4B targets developmental loci directly or via complex recruitment unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated ARID4B directly binds the mTOR promoter to deposit activating H3K27ac, completing a PI3K-ARID4B-mTOR signaling pathway in muscle cells responsive to taurine.\",\n      \"evidence\": \"ChIP-PCR/qPCR, siRNA knockdown, CRISPR/dCas9 activation, and Western blots in C2C12 myoblasts\",\n      \"pmids\": [\"34881695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling between upstream PI3K signaling and ARID4B promoter recruitment not defined\", \"Generalizability of mTOR promoter regulation beyond myoblasts not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked ARID4B to PI3K/AKT signaling and cell-cycle/HDAC1 control in glioma, reinforcing its pro-tumorigenic signaling role in a second tumor type.\",\n      \"evidence\": \"shRNA knockdown in glioma cells with Western blot, cell-cycle flow cytometry, and migration/invasion assays\",\n      \"pmids\": [\"33732001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter targets in glioma not identified by ChIP\", \"The increase in HDAC1 upon ARID4B knockdown is mechanistically unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ARID4B is recruited to specific promoters and switches between coactivator (H3K27ac deposition, H1 displacement) and corepressor (SIN3A/HDAC1, H3K27me3) modes in a context-dependent manner remains unresolved.\",\n      \"evidence\": \"No timeline study reconstitutes ARID4B targeting specificity or the determinant of its activator/repressor switch\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ARID4B-chromatin or ARID4B-complex interactions\", \"Determinants of promoter selectivity unknown\", \"Mechanism toggling activating vs repressive chromatin output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 7, 10, 14]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 10, 14]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 10, 11]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 10, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 3, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 7, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 13, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8, 11]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5, 7, 8]}\n    ],\n    \"complexes\": [\"SIN3A complex\"],\n    \"partners\": [\"ARID4A\", \"HDAC1\", \"BRMS1\", \"SIN3A\", \"SDS3\", \"AR\", \"RB1\", \"H1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}