{"gene":"ARID2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2005,"finding":"ARID2 (BAF200) is a specificity subunit of the PBAF chromatin-remodeling complex (SWI/SNF family) required for selective transcriptional activation of interferon-responsive genes; PBAF and BAF regulate distinct gene sets, and BAF200 is required for PBAF-specific transcription but not BAF-specific transcription.","method":"Biochemical purification of PBAF/BAF complexes, in vitro transcription assays with nuclear receptors, RNAi knockdown with gene expression profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 — reconstitution in vitro plus in vivo functional rescue, replicated across assays in single rigorous study","pmids":["15985610"],"is_preprint":false},{"year":2014,"finding":"ARID2 (BAF200) is required for heart morphogenesis and coronary artery development in vivo; BAF200 knockout mice are embryonic lethal with cardiac defects including thin myocardium, ventricular septum defect, and defective migration/differentiation of subepicardial venous cells into arterial endothelial cells.","method":"Conditional/constitutive knockout mouse model, histological and immunofluorescence analysis of cardiac phenotype","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, multiple cardiac readouts","pmids":["25299188"],"is_preprint":false},{"year":2016,"finding":"ARID2 physically interacts with E2F1 and decreases binding of E2F1/RNA Pol II to the promoters of CCND1 (cyclin D1) and CCNE1 (cyclin E1), thereby repressing their expression and retarding G1/S cell cycle progression in hepatoma cells.","method":"Co-immunoprecipitation, ChIP assay, reporter assays, gain/loss-of-function in hepatoma cell lines and xenograft models","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP and ChIP, single lab with multiple orthogonal methods","pmids":["27351279"],"is_preprint":false},{"year":2017,"finding":"ARID2 (Baf200) promotes homology-directed DNA double-strand break (DSB) repair by facilitating RAD51 recruitment to DSBs; Baf200 and RAD51 physically interact through C-terminal sequences in both proteins. Baf200 forms at least two distinct PBAF complexes: one canonical PBAF containing BRG1 and one containing BAF180 but not BRG1.","method":"Cytological and biochemical assays (Co-IP, immunofluorescence, HR reporter assay, clonogenic survival after DNA damage), biochemical fractionation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including reconstitution-level Co-IP, functional HR assay, and complex characterization in single study","pmids":["28381560"],"is_preprint":false},{"year":2017,"finding":"ARID2 knockout in HCC cells disrupts nucleotide excision repair (NER) by preventing XPG from accumulating at DNA damage sites induced by UV, benzo[a]pyrene, and FeCl3, leading to hypermutation susceptibility.","method":"CRISPR/Cas9 knockout, gene expression profiling, NER functional assay, immunofluorescence for XPG recruitment","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 — clean CRISPR KO with defined NER phenotype and XPG recruitment assay, multiple DNA-damage agents tested","pmids":["28238438"],"is_preprint":false},{"year":2019,"finding":"HBV core protein (HBc) physically interacts with the C-terminal domain of BAF200 (ARID2), disrupting PBAF complex stability and suppressing IFITM1 transcription; basal IFITM1 expression depends on BAF200 rather than the JAK-STAT1 pathway.","method":"Yeast two-hybrid screen, Co-immunoprecipitation in 293T/HepG2/HepG2-NTCP cells, transcriptional reporter assays","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional transcriptional readout, single lab","pmids":["31075894"],"is_preprint":false},{"year":2020,"finding":"ARID2 suppresses epithelial-mesenchymal transition (EMT) in HCC by recruiting DNMT1 to the Snail promoter, increasing promoter methylation and inhibiting Snail transcription; ARID2 mutants with disrupted C2H2 zinc finger domain lose this metastasis-suppressor function.","method":"Co-IP, ChIP-bisulfite sequencing, bisulfite sequencing, loss/gain-of-function in HCC cells and mouse metastasis models, domain mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (ChIP, bisulfite sequencing, Co-IP, mutagenesis, in vivo models), single study with rigorous mechanistic follow-up","pmids":["32071245"],"is_preprint":false},{"year":2020,"finding":"ARID2 is a pomalidomide-induced neosubstrate of the CRL4CRBN E3 ubiquitin ligase complex; pomalidomide induces ARID2 degradation more potently than lenalidomide. BRD7 (another PBAF subunit) is required for pomalidomide-induced ARID2 degradation. ARID2 regulates transcription of MYC and other pomalidomide target genes.","method":"Proteomics, Co-IP, CRISPR/KO, overexpression, protein stability assays, transcriptional profiling in multiple myeloma cells","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods, drug-induced substrate identification with functional validation and BRD7 dependency established","pmids":["32958952"],"is_preprint":false},{"year":2020,"finding":"ARID2 deficiency in melanoma leads to STAT1 upregulation, which increases expression of T-cell-attracting chemokines (CXCL9, CXCL10, CCL5), sensitizing tumors to anti-PD-L1 immune checkpoint inhibitors.","method":"ARID2 CRISPR knockout in melanoma, mouse tumor models with anti-PD-L1 treatment, flow cytometry for CD8+ T cells, transcriptional analysis","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined immune and transcriptional phenotype, in vivo validation, single lab","pmids":["33333124"],"is_preprint":false},{"year":2020,"finding":"ARID2 haploinsufficiency is associated with enhanced RAS-MAPK (ERK1/2 phosphorylation) activity through reduced expression of IFITM1, which interacts with caveolin-1 (CAV-1) to inhibit ERK activation; demonstrated in patient iPSCs and Arid2 haploinsufficient mouse models.","method":"shRNA knockdown in HeLa cells, patient-derived iPSC neuronal differentiation, CRISPR-generated haploinsufficient mouse model, phospho-ERK western blotting, behavioral tests","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — multiple model systems with consistent ERK activation phenotype; pathway mechanism through IFITM1/CAV-1 partially inferred","pmids":["33051312"],"is_preprint":false},{"year":2022,"finding":"ARID2 mitigates hepatic steatosis by promoting ubiquitination and degradation of JAK2 via the E3 ligase NEDD4L, thereby repressing the JAK2-STAT5-PPARγ signaling axis; ARID2 recruits the methyltransferase CARM1 to the NEDD4L promoter, increasing H3R17me2a and activating NEDD4L transcription.","method":"Liver-specific Arid2 knockout mice, ChIP assay, Co-IP, ubiquitination assay, high-fat diet model, pharmacological JAK2 inhibition rescue","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP, Co-IP, ubiquitination assay, in vivo KO with pharmacological rescue; multiple orthogonal methods in single study","pmids":["36396719"],"is_preprint":false},{"year":2022,"finding":"USP2 deubiquitinase physically interacts with ARID2 and reduces its ubiquitin-mediated proteasomal degradation, thereby stabilizing ARID2 protein in lung cancer cells.","method":"Co-immunoprecipitation, immunofluorescence colocalization, CHX chase assay, ubiquitination assay","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP and ubiquitination assay, single lab","pmids":["36567903"],"is_preprint":false},{"year":2022,"finding":"ARID2 and BRD4 synergistically maintain transcriptional enhancer-promoter loops at BRCA1, RAD51, and 53BP1 loci; combined ARID2 deficiency and BRD4 inhibition synergistically impairs homologous recombination and NHEJ, causing DSB accumulation and synthetic lethality in HCC cells.","method":"High-throughput drug screening, CRISPR KO, ChIP, chromosome conformation assay, DNA damage functional assays (γH2AX, RAD51 foci)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and chromatin conformation data with functional DNA repair assays, single lab","pmids":["35017665"],"is_preprint":false},{"year":2018,"finding":"ARID2 (Baf200) is required for hematopoietic stem cell (HSC) self-renewal and differentiation; conditional Baf200 knockout impairs long-term HSC reconstitution, erythropoiesis, and accelerates MLL-AF9-driven leukemia, with transcriptomes showing altered expression of erythropoiesis/hematopoiesis genes.","method":"Tissue-specific Cre-lox knockout (Tie2-Cre, Vav-iCre, Mx1-Cre), bone marrow transplantation, RNA-seq, leukemia mouse model","journal":"Journal of hematology & oncology","confidence":"High","confidence_rationale":"Tier 2 — multiple Cre drivers, transplantation experiments, RNA-seq, in vivo leukemia model; strong orthogonal evidence","pmids":["29482581"],"is_preprint":false},{"year":2017,"finding":"HBV X protein (HBx) suppresses ARID2 transcription through downregulation of ATOH1; ATOH1 binding elements in the ARID2 promoter (nt-1040/nt-601) are required for this regulation, as mutation of ATOH1 binding sites partially abolishes HBx-triggered ARID2 repression.","method":"Reporter assays, promoter deletion analysis, ectopic ATOH1 expression, site-directed mutagenesis, Western blotting, HBV transgenic mice","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — promoter mutagenesis with functional rescue, in vivo validation in transgenic mice; single lab","pmids":["28498550"],"is_preprint":false},{"year":2018,"finding":"The ARID domain of human BAF200 (ARID2) adopts a defined secondary structure and has the potential to bind DNA sequences; NMR chemical shift assignments establish its fold as an ARID-type domain.","method":"NMR spectroscopy (backbone 1H, 13C, 15N chemical shift assignment)","journal":"Biomolecular NMR assignments","confidence":"Low","confidence_rationale":"Tier 3 — structural assignment only, no functional validation of DNA binding specificity","pmids":["30535613"],"is_preprint":false},{"year":2016,"finding":"ARID2 represses CD44 promoter activity and protein expression in HCC cells; overexpression of ARID2 inhibits migration and invasion of HepG2 and Huh7 cells and restricts subcutaneous tumor growth in nude mice.","method":"Dual luciferase reporter assay, Western blot, cell migration assay, xenograft mouse model","journal":"Zhonghua gan zang bing za zhi","confidence":"Low","confidence_rationale":"Tier 3 — single lab, reporter assay without ChIP validation of direct binding","pmids":["27095763"],"is_preprint":false},{"year":2024,"finding":"PBAF complex (defined by ARID2) co-occupies repressive chromatin regions with PRC2 and facilitates REST transcription factor occupancy at these loci; loss of ARID2 disrupts PBAF complex integrity, impairs REST binding, and leads to upregulation of synaptic/neuronal transcripts in melanoma.","method":"ChIP-seq, ATAC-seq, CUT&RUN, ARID2 CRISPR knockout, time-resolved chromatin remodeling assays in melanoma cells and melanocytes","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 — comprehensive epigenomic profiling with multiple orthogonal methods; preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Arid2 is required for follicular B cell differentiation and germinal center responses in vivo; Arid2 deletion impairs stage-specific gene expression programs including B cell receptor signaling, and reduces IgG antibody production after immunization.","method":"Conditional knockout mice (Mb1-Cre, CD19-Cre), bone marrow transplantation, RNA-seq of isolated B cell populations, immunization experiments, flow cytometry","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple Cre drivers with defined phenotype, transcriptomic profiling, functional immunization assay; preprint","pmids":["41256460"],"is_preprint":true},{"year":2021,"finding":"ARID2 deficiency in lung cancer impairs DNA repair and alters chromatin structure, promoting proliferation and metastasis in vitro and in vivo; ARID2 loss increases sensitivity to DNA-damaging chemotherapy agents.","method":"Targeted sequencing of patient cohort, protein expression analysis, ARID2 KO/KD functional experiments (proliferation, migration, invasion assays), in vivo tumor models, chromatin structure analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with multiple phenotypic readouts and chromatin structural analysis; single lab","pmids":["33742126"],"is_preprint":false},{"year":2024,"finding":"In TFE3-rearranged RCC, PRCC-TFE3 fusion directly binds and upregulates ERBB3 expression; ARID2 knockout further enhances this effect and activates MAPK and ERBB3 signaling pathways, with ARID2-KO cells showing heightened sensitivity to ERBB3 inhibition.","method":"ChIP assay (PRCC-TFE3 binding to ERBB3), CRISPR KO, transcriptomic analysis, in vitro/in vivo tumor models, pharmacological inhibition","journal":"Current issues in molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrating direct TFE3 binding plus ARID2 KO phenotype; pathway placed by epistasis-like pharmacological rescue","pmids":["39727945"],"is_preprint":false}],"current_model":"ARID2 is a defining subunit of the PBAF SWI/SNF chromatin-remodeling complex that selectively regulates transcription of interferon-responsive and other genes by remodeling nucleosomes at target promoters; it physically interacts with partners including E2F1 (to repress cyclin D1/E1), DNMT1 (to silence Snail via promoter methylation), RAD51 (to facilitate homology-directed DNA repair), NEDD4L/CARM1 (to ubiquitinate JAK2 and suppress JAK2-STAT5-PPARγ signaling), and REST (to maintain repressive chromatin), while also serving as a pomalidomide-induced CRL4CRBN neosubstrate whose degradation de-represses MYC in multiple myeloma; loss of ARID2 disrupts NER (via XPG misrecruitment), homologous recombination, NHEJ, and PBAF-specific REST occupancy at repressed chromatin, collectively explaining its roles as a tumor suppressor in hepatocellular carcinoma, lung adenocarcinoma, melanoma, and other cancers, as well as its essential functions in cardiac morphogenesis, hematopoiesis, and B cell differentiation."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing ARID2 as a PBAF-specific subunit resolved how SWI/SNF subcomplexes achieve target-gene selectivity, showing that PBAF and BAF remodel distinct promoter sets and that ARID2 is required specifically for interferon-responsive gene transcription.","evidence":"Biochemical purification of PBAF/BAF, in vitro transcription assays, and RNAi-mediated gene expression profiling","pmids":["15985610"],"confidence":"High","gaps":["No genome-wide binding profile for ARID2-containing PBAF","Mechanism by which ARID2 confers locus selectivity undefined","Whether ARID2 contributes to non-transcriptional PBAF functions unknown"]},{"year":2014,"claim":"Demonstrating that ARID2 knockout causes embryonic lethality with cardiac defects established ARID2 as essential for heart morphogenesis and coronary vasculogenesis, extending its role beyond transcription regulation to organ development.","evidence":"Constitutive and conditional knockout mice with histological and immunofluorescence analysis of cardiac structures","pmids":["25299188"],"confidence":"High","gaps":["Target genes mediating the cardiac phenotype not identified","Whether the cardiac role is PBAF-dependent or PBAF-independent not determined"]},{"year":2016,"claim":"Identification of a physical ARID2–E2F1 interaction that reduces E2F1/Pol II occupancy at CCND1 and CCNE1 promoters revealed how ARID2 directly restrains G1/S progression in hepatoma cells, linking chromatin remodeling to cell-cycle control.","evidence":"Co-immunoprecipitation, ChIP, reporter assays, and xenograft models in hepatoma cells","pmids":["27351279"],"confidence":"Medium","gaps":["Whether ARID2 remodels nucleosomes at E2F1-occupied promoters or blocks E2F1 binding through steric competition is unresolved","Generalizability beyond hepatoma not tested"]},{"year":2017,"claim":"Discovery that ARID2 physically interacts with RAD51 and facilitates its recruitment to DSBs, alongside identification of a BRG1-independent PBAF variant, established ARID2 as a direct participant in homology-directed DNA repair and revealed unexpected PBAF compositional heterogeneity.","evidence":"Co-IP, immunofluorescence, HR reporter assay, clonogenic survival, and biochemical fractionation","pmids":["28381560"],"confidence":"High","gaps":["How ARID2 promotes RAD51 loading mechanistically (chromatin remodeling vs. direct scaffolding) unclear","Function of the BRG1-independent PBAF variant uncharacterized"]},{"year":2017,"claim":"Showing that ARID2 knockout prevents XPG accumulation at UV/carcinogen-induced damage sites linked PBAF-mediated chromatin remodeling to nucleotide excision repair and explained the hypermutation phenotype of ARID2-deficient HCC.","evidence":"CRISPR knockout in HCC cells, NER functional assay, immunofluorescence for XPG recruitment with multiple DNA-damage agents","pmids":["28238438"],"confidence":"High","gaps":["Whether ARID2 remodels nucleosomes at damage sites to expose DNA for XPG or acts through an indirect mechanism unknown","Relationship between NER and HR roles of ARID2 not addressed"]},{"year":2018,"claim":"Conditional knockout studies in hematopoietic lineages revealed ARID2 is essential for HSC self-renewal and erythropoiesis and acts as a tumor suppressor that restrains MLL-AF9-driven leukemogenesis, broadening its developmental role to blood cell homeostasis.","evidence":"Multiple Cre-driver knockouts, bone marrow transplantation, RNA-seq, and MLL-AF9 leukemia mouse model","pmids":["29482581"],"confidence":"High","gaps":["Direct transcriptional targets of ARID2 in HSCs not defined by ChIP","Whether PBAF integrity is required for the hematopoietic phenotype not tested"]},{"year":2019,"claim":"Identification of HBV core protein binding to the ARID2 C-terminus, disrupting PBAF stability and suppressing IFITM1 transcription, provided a viral mechanism for innate immune evasion through PBAF subversion.","evidence":"Yeast two-hybrid, Co-IP in multiple hepatocyte lines, transcriptional reporter assays","pmids":["31075894"],"confidence":"Medium","gaps":["Global impact of HBc on PBAF complex composition not characterized","In vivo relevance of HBc–ARID2 interaction during HBV infection not demonstrated"]},{"year":2020,"claim":"Demonstration that ARID2 recruits DNMT1 to the Snail promoter to methylate and silence it revealed a chromatin-remodeler–DNA-methyltransferase partnership that suppresses EMT and metastasis in HCC, with the C2H2 zinc finger domain being essential.","evidence":"Co-IP, ChIP-bisulfite sequencing, domain mutagenesis, and in vivo metastasis models","pmids":["32071245"],"confidence":"High","gaps":["Whether ARID2-DNMT1 cooperation is genome-wide or promoter-specific unknown","Structural basis of the zinc finger requirement not resolved"]},{"year":2020,"claim":"Identification of ARID2 as a pomalidomide-induced CRL4-CRBN neosubstrate, degraded in a BRD7-dependent manner, uncovered a pharmacological mechanism by which immunomodulatory drugs de-repress MYC through PBAF destabilization in multiple myeloma.","evidence":"Proteomics, Co-IP, CRISPR knockout, protein stability assays, and transcriptional profiling in myeloma cells","pmids":["32958952"],"confidence":"High","gaps":["Structural basis for pomalidomide-induced CRBN–ARID2 interaction not determined","Whether ARID2 degradation is therapeutically beneficial or detrimental in myeloma not established"]},{"year":2020,"claim":"Finding that ARID2 loss in melanoma upregulates STAT1 and T-cell-attracting chemokines, sensitizing tumors to anti-PD-L1 therapy, reframed ARID2 deficiency as a potential immunotherapy biomarker rather than solely a loss-of-function event.","evidence":"CRISPR knockout in melanoma, in vivo anti-PD-L1 treatment, flow cytometry, transcriptional analysis","pmids":["33333124"],"confidence":"Medium","gaps":["Whether STAT1 upregulation is a direct consequence of altered PBAF chromatin remodeling not shown","Applicability to other tumor types unknown"]},{"year":2022,"claim":"Revealing that ARID2 recruits CARM1 to the NEDD4L promoter to activate NEDD4L transcription, driving JAK2 ubiquitination and suppressing JAK2-STAT5-PPARγ signaling, established a chromatin-remodeler–methyltransferase–ubiquitin ligase cascade controlling hepatic lipid metabolism.","evidence":"Liver-specific Arid2 knockout mice, ChIP, Co-IP, ubiquitination assay, high-fat diet model with pharmacological JAK2 inhibition rescue","pmids":["36396719"],"confidence":"High","gaps":["Whether CARM1 recruitment requires PBAF remodeling activity not distinguished","Whether this pathway operates in non-hepatic tissues unknown"]},{"year":2022,"claim":"Demonstration that ARID2 and BRD4 co-maintain enhancer-promoter loops at BRCA1, RAD51, and 53BP1 loci revealed a synthetic lethal interaction exploitable therapeutically, showing ARID2 deficiency plus BRD4 inhibition catastrophically impairs both HR and NHEJ.","evidence":"High-throughput drug screening, CRISPR KO, ChIP, chromosome conformation assay, and DNA damage assays in HCC cells","pmids":["35017665"],"confidence":"Medium","gaps":["Whether ARID2 directly stabilizes 3D chromatin loops or acts through transcriptional regulation of loop-forming factors not resolved","Applicability of synthetic lethality in clinical settings untested"]},{"year":2022,"claim":"Identification of USP2 as a deubiquitinase that physically interacts with and stabilizes ARID2 protein provided the first evidence of regulated ARID2 turnover outside the CRBN-dependent degradation pathway.","evidence":"Co-IP, immunofluorescence colocalization, CHX chase, and ubiquitination assays in lung cancer cells","pmids":["36567903"],"confidence":"Medium","gaps":["The E3 ligase responsible for basal ARID2 ubiquitination not identified","In vivo significance of USP2-mediated ARID2 stabilization not demonstrated"]},{"year":null,"claim":"Major unresolved questions include the structural basis for ARID2-mediated locus selectivity within PBAF, the full complement of ARID2-dependent genomic targets across tissues, and whether ARID2's DNA-repair and transcriptional functions are mechanistically separable.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of ARID2 within PBAF complex","No genome-wide ChIP-seq map of ARID2 across multiple normal tissues","Separation-of-function mutations distinguishing transcription from DNA repair roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,6,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,15]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,3,6,12]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3,4,12]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,6,12,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5,10]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[3,4,12]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,20]}],"complexes":["PBAF (SWI/SNF)","CRL4-CRBN (as neosubstrate)"],"partners":["BRG1","BAF180","BRD7","RAD51","E2F1","DNMT1","CARM1","USP2"],"other_free_text":[]},"mechanistic_narrative":"ARID2 (BAF200) is a defining subunit of the PBAF chromatin-remodeling complex that directs nucleosome remodeling at specific genomic loci to regulate transcription, DNA repair, and cell fate decisions across multiple tissues. As a PBAF specificity factor, ARID2 is required for interferon-responsive gene activation, repression of cell-cycle genes (CCND1, CCNE1) through interaction with E2F1, suppression of EMT via DNMT1 recruitment to the Snail promoter, and maintenance of REST-dependent repressive chromatin; it also activates NEDD4L transcription by recruiting CARM1, thereby promoting JAK2 ubiquitination and suppressing hepatic steatosis [PMID:15985610, PMID:27351279, PMID:32071245, PMID:36396719]. ARID2 facilitates homology-directed DNA repair through physical interaction with RAD51 and maintains nucleotide excision repair by enabling XPG recruitment to damage sites, while cooperating with BRD4 to sustain enhancer-promoter loops at DNA repair gene loci [PMID:28381560, PMID:28238438, PMID:35017665]. Loss of ARID2 causes embryonic-lethal cardiac defects, impairs hematopoietic stem cell self-renewal, and acts as a tumor suppressor in hepatocellular carcinoma, melanoma, and lung cancer; ARID2 is also a pomalidomide-induced CRL4-CRBN neosubstrate whose degradation de-represses MYC in multiple myeloma [PMID:25299188, PMID:29482581, PMID:32958952, PMID:33333124]."},"prefetch_data":{"uniprot":{"accession":"Q68CP9","full_name":"AT-rich interactive domain-containing protein 2","aliases":["BRG1-associated factor 200","BAF200","Zinc finger protein with activation potential","Zipzap/p200"],"length_aa":1835,"mass_kda":197.4,"function":"Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Required for the stability of the SWI/SNF chromatin remodeling complex SWI/SNF-B (PBAF). May be involved in targeting the complex to different genes. May be involved in regulating transcriptional activation of cardiac genes","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q68CP9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARID2","classification":"Not Classified","n_dependent_lines":472,"n_total_lines":1208,"dependency_fraction":0.39072847682119205},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SMARCA4","stoichiometry":4.0},{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ARID2","total_profiled":1310},"omim":[{"mim_id":"617808","title":"COFFIN-SIRIS SYNDROME 6; CSS6","url":"https://www.omim.org/entry/617808"},{"mim_id":"611549","title":"SODIUM LEAK CHANNEL, NONSELECTIVE; NALCN","url":"https://www.omim.org/entry/611549"},{"mim_id":"610999","title":"ENHANCER OF POLYCOMB HOMOLOG 1; EPC1","url":"https://www.omim.org/entry/610999"},{"mim_id":"609539","title":"AT-RICH INTERACTION DOMAIN-CONTAINING PROTEIN 2; ARID2","url":"https://www.omim.org/entry/609539"},{"mim_id":"607585","title":"ATM SERINE/THREONINE KINASE; ATM","url":"https://www.omim.org/entry/607585"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ARID2"},"hgnc":{"alias_symbol":["KIAA1557","DKFZp686G052","FLJ30619","BAF200","SMARCF3","ZIPZAP","p200"],"prev_symbol":[]},"alphafold":{"accession":"Q68CP9","domains":[{"cath_id":"1.10.150.60","chopping":"23-112","consensus_level":"medium","plddt":82.4034,"start":23,"end":112},{"cath_id":"1.25.10.10","chopping":"156-253_270-396","consensus_level":"medium","plddt":88.5461,"start":156,"end":396},{"cath_id":"1.10.10.10","chopping":"520-609","consensus_level":"high","plddt":84.1876,"start":520,"end":609},{"cath_id":"-","chopping":"1627-1700","consensus_level":"medium","plddt":84.4736,"start":1627,"end":1700}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68CP9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q68CP9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q68CP9-F1-predicted_aligned_error_v6.png","plddt_mean":51.16},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARID2","jax_strain_url":"https://www.jax.org/strain/search?query=ARID2"},"sequence":{"accession":"Q68CP9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q68CP9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q68CP9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68CP9"}},"corpus_meta":[{"pmid":"21822264","id":"PMC_21822264","title":"Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma.","date":"2011","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21822264","citation_count":337,"is_preprint":false},{"pmid":"15985610","id":"PMC_15985610","title":"PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes.","date":"2005","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/15985610","citation_count":191,"is_preprint":false},{"pmid":"25743111","id":"PMC_25743111","title":"Long Noncoding RNA Arid2-IR Is a Novel Therapeutic Target for Renal Inflammation.","date":"2015","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/25743111","citation_count":117,"is_preprint":false},{"pmid":"24382590","id":"PMC_24382590","title":"Exome sequencing reveals frequent inactivating mutations in ARID1A, ARID1B, ARID2 and ARID4A in microsatellite unstable colorectal cancer.","date":"2014","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24382590","citation_count":101,"is_preprint":false},{"pmid":"32071245","id":"PMC_32071245","title":"Chromatin remodeling factor ARID2 suppresses hepatocellular carcinoma metastasis via DNMT1-Snail axis.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32071245","citation_count":89,"is_preprint":false},{"pmid":"32958952","id":"PMC_32958952","title":"ARID2 is a pomalidomide-dependent CRL4CRBN substrate in multiple myeloma cells.","date":"2020","source":"Nature chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/32958952","citation_count":75,"is_preprint":false},{"pmid":"31918270","id":"PMC_31918270","title":"MiR-155-5p promotes oral cancer progression by targeting chromatin remodeling gene ARID2.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31918270","citation_count":72,"is_preprint":false},{"pmid":"23047306","id":"PMC_23047306","title":"Recurrent inactivating mutations of ARID2 in non-small cell lung carcinoma.","date":"2012","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/23047306","citation_count":65,"is_preprint":false},{"pmid":"34512623","id":"PMC_34512623","title":"ARID1A, ARID1B, and ARID2 Mutations Serve as Potential Biomarkers for Immune Checkpoint Blockade in Patients With Non-Small Cell Lung Cancer.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34512623","citation_count":57,"is_preprint":false},{"pmid":"28238438","id":"PMC_28238438","title":"ARID2 modulates DNA damage response in human hepatocellular carcinoma cells.","date":"2017","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/28238438","citation_count":55,"is_preprint":false},{"pmid":"28124119","id":"PMC_28124119","title":"Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype.","date":"2017","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28124119","citation_count":54,"is_preprint":false},{"pmid":"26238514","id":"PMC_26238514","title":"Mutations in ARID2 are associated with intellectual disabilities.","date":"2015","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26238514","citation_count":53,"is_preprint":false},{"pmid":"27035278","id":"PMC_27035278","title":"MicroRNA-155 promotes tumor growth of human hepatocellular carcinoma by targeting ARID2.","date":"2016","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27035278","citation_count":50,"is_preprint":false},{"pmid":"22095441","id":"PMC_22095441","title":"ARID2: a new tumor suppressor gene in hepatocellular carcinoma.","date":"2011","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/22095441","citation_count":47,"is_preprint":false},{"pmid":"27351279","id":"PMC_27351279","title":"Chromatin remodeling gene ARID2 targets cyclin D1 and cyclin E1 to suppress hepatoma cell progression.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27351279","citation_count":36,"is_preprint":false},{"pmid":"33742126","id":"PMC_33742126","title":"ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to chemotherapy in lung cancer.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33742126","citation_count":32,"is_preprint":false},{"pmid":"25299188","id":"PMC_25299188","title":"BAF200 is required for heart morphogenesis and coronary artery development.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25299188","citation_count":31,"is_preprint":false},{"pmid":"29482581","id":"PMC_29482581","title":"The chromatin remodeling subunit Baf200 promotes normal hematopoiesis and inhibits leukemogenesis.","date":"2018","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29482581","citation_count":31,"is_preprint":false},{"pmid":"33333124","id":"PMC_33333124","title":"ARID2 Deficiency Correlates with the Response to Immune Checkpoint Blockade in Melanoma.","date":"2020","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/33333124","citation_count":31,"is_preprint":false},{"pmid":"28381560","id":"PMC_28381560","title":"The chromatin-remodeling subunit Baf200 promotes homology-directed DNA repair and regulates distinct chromatin-remodeling complexes.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28381560","citation_count":30,"is_preprint":false},{"pmid":"26637902","id":"PMC_26637902","title":"Loss of ARID1A, ARID1B, and ARID2 Expression During Progression of Gastric Cancer.","date":"2015","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26637902","citation_count":29,"is_preprint":false},{"pmid":"26169693","id":"PMC_26169693","title":"miR-208-3p promotes hepatocellular carcinoma cell proliferation and invasion through regulating ARID2 expression.","date":"2015","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/26169693","citation_count":28,"is_preprint":false},{"pmid":"33262464","id":"PMC_33262464","title":"Exome sequencing identifies ARID2 as a novel tumor suppressor in early-onset sporadic rectal cancer.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33262464","citation_count":27,"is_preprint":false},{"pmid":"30462533","id":"PMC_30462533","title":"Early growth response protein-1 upregulates long noncoding RNA Arid2-IR to promote extracellular matrix production in diabetic kidney disease.","date":"2018","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30462533","citation_count":25,"is_preprint":false},{"pmid":"34858604","id":"PMC_34858604","title":"Targeting HSPA1A in ARID2-deficient lung adenocarcinoma.","date":"2021","source":"National science review","url":"https://pubmed.ncbi.nlm.nih.gov/34858604","citation_count":20,"is_preprint":false},{"pmid":"32977645","id":"PMC_32977645","title":"ARID2 Chromatin Remodeler in Hepatocellular Carcinoma.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32977645","citation_count":20,"is_preprint":false},{"pmid":"31075894","id":"PMC_31075894","title":"Human Hepatitis B Virus Core Protein Inhibits IFNα-Induced IFITM1 Expression by Interacting with BAF200.","date":"2019","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/31075894","citation_count":18,"is_preprint":false},{"pmid":"35017665","id":"PMC_35017665","title":"BRD4 inhibition induces synthetic lethality in ARID2-deficient hepatocellular carcinoma by increasing DNA damage.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35017665","citation_count":17,"is_preprint":false},{"pmid":"28498550","id":"PMC_28498550","title":"HBx protein-mediated ATOH1 downregulation suppresses ARID2 expression and promotes hepatocellular carcinoma.","date":"2017","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/28498550","citation_count":17,"is_preprint":false},{"pmid":"33090288","id":"PMC_33090288","title":"Arid2-IR promotes NF-κB-mediated renal inflammation by targeting NLRC5 transcription.","date":"2020","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/33090288","citation_count":17,"is_preprint":false},{"pmid":"33346030","id":"PMC_33346030","title":"Arid2 regulates hematopoietic stem cell differentiation in normal hematopoiesis.","date":"2020","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/33346030","citation_count":16,"is_preprint":false},{"pmid":"28944851","id":"PMC_28944851","title":"microRNA‑96 regulates the proliferation of nucleus pulposus cells by targeting ARID2/AKT signaling.","date":"2017","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/28944851","citation_count":16,"is_preprint":false},{"pmid":"28884947","id":"PMC_28884947","title":"Confirmation of an ARID2 defect in SWI/SNF-related intellectual disability.","date":"2017","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/28884947","citation_count":16,"is_preprint":false},{"pmid":"36396719","id":"PMC_36396719","title":"ARID2 mitigates hepatic steatosis via promoting the ubiquitination of JAK2.","date":"2022","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/36396719","citation_count":15,"is_preprint":false},{"pmid":"33786634","id":"PMC_33786634","title":"CREB1 acts via the miR‑922/ARID2 axis to enhance malignant behavior of liver cancer cells.","date":"2021","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/33786634","citation_count":14,"is_preprint":false},{"pmid":"29698805","id":"PMC_29698805","title":"Extending the clinical and genetic spectrum of ARID2 related intellectual disability. A case series of 7 patients.","date":"2018","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29698805","citation_count":13,"is_preprint":false},{"pmid":"30838730","id":"PMC_30838730","title":"Patient with anomalous skin pigmentation expands the phenotype of ARID2 loss-of-function disorder, a SWI/SNF-related intellectual disability.","date":"2019","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/30838730","citation_count":13,"is_preprint":false},{"pmid":"36567903","id":"PMC_36567903","title":"USP2 Inhibits Lung Cancer Pathogenesis by Reducing ARID2 Protein Degradation via Ubiquitination.","date":"2022","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/36567903","citation_count":12,"is_preprint":false},{"pmid":"35144623","id":"PMC_35144623","title":"Concomitant novel ALK-SSH2, EML4-ALK and ARID2-ALK, EML4-ALK double-fusion variants and confer sensitivity to crizotinib in two lung adenocarcinoma patients, respectively.","date":"2022","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35144623","citation_count":11,"is_preprint":false},{"pmid":"36315994","id":"PMC_36315994","title":"SIS3 Alleviates Cisplatin-Induced Acute Kidney Injury by Regulating the LncRNA Arid2-IR-Transferrin Receptor Pathway.","date":"2022","source":"Kidney & blood pressure research","url":"https://pubmed.ncbi.nlm.nih.gov/36315994","citation_count":9,"is_preprint":false},{"pmid":"33051312","id":"PMC_33051312","title":"Association between ARID2 and RAS-MAPK pathway in intellectual disability and short stature.","date":"2020","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33051312","citation_count":9,"is_preprint":false},{"pmid":"38341515","id":"PMC_38341515","title":"ARID2 mutations may relay a distinct subset of cutaneous melanoma patients with different outcomes.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38341515","citation_count":8,"is_preprint":false},{"pmid":"35813374","id":"PMC_35813374","title":"ARID2, a Rare Cause of Coffin-Siris Syndrome: A Clinical Description of Two Cases.","date":"2022","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/35813374","citation_count":8,"is_preprint":false},{"pmid":"36756859","id":"PMC_36756859","title":"ARID2, a rare cause of Coffin-Siris syndrome: A novel microdeletion at 12q12q13.11 causing severe short stature and literature review.","date":"2023","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/36756859","citation_count":7,"is_preprint":false},{"pmid":"31912402","id":"PMC_31912402","title":"Long non-coding RNA Arid2-IR affects advanced glycation end products-induced human retinal endothelial cell injury by binding to Smad3.","date":"2020","source":"International ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/31912402","citation_count":7,"is_preprint":false},{"pmid":"38243407","id":"PMC_38243407","title":"ARID2, a milder cause of Coffin-Siris Syndrome? Broadening the phenotype with 17 additional individuals.","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38243407","citation_count":6,"is_preprint":false},{"pmid":"36530029","id":"PMC_36530029","title":"miR-29a-5p regulates the malignant biological process of liver cancer cells through ARID2 regulation of EMT.","date":"2023","source":"Advances in clinical and experimental medicine : official organ Wroclaw Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/36530029","citation_count":5,"is_preprint":false},{"pmid":"26634163","id":"PMC_26634163","title":"Clinicopathological and Targeted Exome Gene Features of a Patient with Metastatic Acinic Cell Carcinoma of the Parotid Gland Harboring an ARID2 Nonsense Mutation and CDKN2A/B Deletion.","date":"2015","source":"Case reports in oncological medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26634163","citation_count":5,"is_preprint":false},{"pmid":"40044822","id":"PMC_40044822","title":"ARID2-related disorder: further delineation of the clinical phenotype of 27 novel individuals and description of an epigenetic signature.","date":"2025","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/40044822","citation_count":4,"is_preprint":false},{"pmid":"29072391","id":"PMC_29072391","title":"Analysis of ARID2 Gene Mutation in Oral Squamous Cell Carcinoma.","date":"2017","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/29072391","citation_count":4,"is_preprint":false},{"pmid":"36074605","id":"PMC_36074605","title":"Arid2-IR downregulates miR-132-3p through methylation to promote LPS-induced ALI in pneumonia.","date":"2022","source":"Inhalation toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/36074605","citation_count":3,"is_preprint":false},{"pmid":"37664441","id":"PMC_37664441","title":"Early progression and transformation of a splenic diffuse red pulp small B-cell lymphoma with NOTCH1, ARID2, CREBBP, and TNFRSF14 gene mutations.","date":"2023","source":"Leukemia research reports","url":"https://pubmed.ncbi.nlm.nih.gov/37664441","citation_count":3,"is_preprint":false},{"pmid":"30535613","id":"PMC_30535613","title":"Sequential backbone resonance assignment of AT-rich interaction domain of human BAF200.","date":"2018","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/30535613","citation_count":2,"is_preprint":false},{"pmid":"39727945","id":"PMC_39727945","title":"ARID2 Deficiency Enhances Tumor Progression via ERBB3 Signaling in TFE3-Rearranged Renal Cell Carcinoma.","date":"2024","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/39727945","citation_count":1,"is_preprint":false},{"pmid":"27095763","id":"PMC_27095763","title":"[The regulation of CD44 expression by new tumor suppressor gene Arid2 and the influence of Arid2 on the invasion and metastasis in hepatocellular carcinoma cells].","date":"2016","source":"Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/27095763","citation_count":1,"is_preprint":false},{"pmid":"41256460","id":"PMC_41256460","title":"Arid2 promotes Follicular B-cell differentiation and antibody responses in vivo.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41256460","citation_count":0,"is_preprint":false},{"pmid":"39054516","id":"PMC_39054516","title":"Revealing the clinical impact of MTOR and ARID2 gene mutations on MALT lymphoma of the alimentary canal using targeted sequencing.","date":"2024","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39054516","citation_count":0,"is_preprint":false},{"pmid":"38721575","id":"PMC_38721575","title":"Frameshift Variant in ARID2 in a Chilean Individual with Coffin-Siris Syndrome Phenotype.","date":"2021","source":"Journal of pediatric genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38721575","citation_count":0,"is_preprint":false},{"pmid":"41764760","id":"PMC_41764760","title":"Targeting the STK39/ARID2 Axis to Inhibit NF-κB Signaling: A Novel Pathway for Mesenchymal Stem Cell Osteogenic Differentiation in Osteoporosis Management.","date":"2026","source":"Journal of musculoskeletal & neuronal interactions","url":"https://pubmed.ncbi.nlm.nih.gov/41764760","citation_count":0,"is_preprint":false},{"pmid":"41765118","id":"PMC_41765118","title":"A novel variant in ARID2 causes Coffin-Siris syndrome 6 with liver cirrhosis.","date":"2026","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/41765118","citation_count":0,"is_preprint":false},{"pmid":"42028735","id":"PMC_42028735","title":"[Retracted] MicroRNA‑155 promotes tumor growth of human hepatocellular carcinoma by targeting ARID2.","date":"2026","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42028735","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.01.678812","title":"Arid2 promotes Follicular B-cell differentiation and antibody responses <i>in vivo</i>","date":"2025-10-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.01.678812","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.07.669153","title":"Integrative comparative transcriptomics using cultivated and wild rice reveals key regulators of developmental and photosynthetic progression along the rice leaf developmental gradient","date":"2025-08-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.07.669153","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.23.609212","title":"The SWI/SNF PBAF complex facilitates REST occupancy at repressive chromatin","date":"2024-08-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.23.609212","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.23.604673","title":"Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma","date":"2024-07-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.23.604673","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":32225,"output_tokens":5027,"usd":0.08604},"stage2":{"model":"claude-opus-4-6","input_tokens":8552,"output_tokens":3679,"usd":0.202102},"total_usd":0.288142,"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\": 2005,\n      \"finding\": \"ARID2 (BAF200) is a specificity subunit of the PBAF chromatin-remodeling complex (SWI/SNF family) required for selective transcriptional activation of interferon-responsive genes; PBAF and BAF regulate distinct gene sets, and BAF200 is required for PBAF-specific transcription but not BAF-specific transcription.\",\n      \"method\": \"Biochemical purification of PBAF/BAF complexes, in vitro transcription assays with nuclear receptors, RNAi knockdown with gene expression profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reconstitution in vitro plus in vivo functional rescue, replicated across assays in single rigorous study\",\n      \"pmids\": [\"15985610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ARID2 (BAF200) is required for heart morphogenesis and coronary artery development in vivo; BAF200 knockout mice are embryonic lethal with cardiac defects including thin myocardium, ventricular septum defect, and defective migration/differentiation of subepicardial venous cells into arterial endothelial cells.\",\n      \"method\": \"Conditional/constitutive knockout mouse model, histological and immunofluorescence analysis of cardiac phenotype\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, multiple cardiac readouts\",\n      \"pmids\": [\"25299188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ARID2 physically interacts with E2F1 and decreases binding of E2F1/RNA Pol II to the promoters of CCND1 (cyclin D1) and CCNE1 (cyclin E1), thereby repressing their expression and retarding G1/S cell cycle progression in hepatoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, reporter assays, gain/loss-of-function in hepatoma cell lines and xenograft models\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and ChIP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27351279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ARID2 (Baf200) promotes homology-directed DNA double-strand break (DSB) repair by facilitating RAD51 recruitment to DSBs; Baf200 and RAD51 physically interact through C-terminal sequences in both proteins. Baf200 forms at least two distinct PBAF complexes: one canonical PBAF containing BRG1 and one containing BAF180 but not BRG1.\",\n      \"method\": \"Cytological and biochemical assays (Co-IP, immunofluorescence, HR reporter assay, clonogenic survival after DNA damage), biochemical fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including reconstitution-level Co-IP, functional HR assay, and complex characterization in single study\",\n      \"pmids\": [\"28381560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ARID2 knockout in HCC cells disrupts nucleotide excision repair (NER) by preventing XPG from accumulating at DNA damage sites induced by UV, benzo[a]pyrene, and FeCl3, leading to hypermutation susceptibility.\",\n      \"method\": \"CRISPR/Cas9 knockout, gene expression profiling, NER functional assay, immunofluorescence for XPG recruitment\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean CRISPR KO with defined NER phenotype and XPG recruitment assay, multiple DNA-damage agents tested\",\n      \"pmids\": [\"28238438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HBV core protein (HBc) physically interacts with the C-terminal domain of BAF200 (ARID2), disrupting PBAF complex stability and suppressing IFITM1 transcription; basal IFITM1 expression depends on BAF200 rather than the JAK-STAT1 pathway.\",\n      \"method\": \"Yeast two-hybrid screen, Co-immunoprecipitation in 293T/HepG2/HepG2-NTCP cells, transcriptional reporter assays\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional transcriptional readout, single lab\",\n      \"pmids\": [\"31075894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARID2 suppresses epithelial-mesenchymal transition (EMT) in HCC by recruiting DNMT1 to the Snail promoter, increasing promoter methylation and inhibiting Snail transcription; ARID2 mutants with disrupted C2H2 zinc finger domain lose this metastasis-suppressor function.\",\n      \"method\": \"Co-IP, ChIP-bisulfite sequencing, bisulfite sequencing, loss/gain-of-function in HCC cells and mouse metastasis models, domain mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (ChIP, bisulfite sequencing, Co-IP, mutagenesis, in vivo models), single study with rigorous mechanistic follow-up\",\n      \"pmids\": [\"32071245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARID2 is a pomalidomide-induced neosubstrate of the CRL4CRBN E3 ubiquitin ligase complex; pomalidomide induces ARID2 degradation more potently than lenalidomide. BRD7 (another PBAF subunit) is required for pomalidomide-induced ARID2 degradation. ARID2 regulates transcription of MYC and other pomalidomide target genes.\",\n      \"method\": \"Proteomics, Co-IP, CRISPR/KO, overexpression, protein stability assays, transcriptional profiling in multiple myeloma cells\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods, drug-induced substrate identification with functional validation and BRD7 dependency established\",\n      \"pmids\": [\"32958952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARID2 deficiency in melanoma leads to STAT1 upregulation, which increases expression of T-cell-attracting chemokines (CXCL9, CXCL10, CCL5), sensitizing tumors to anti-PD-L1 immune checkpoint inhibitors.\",\n      \"method\": \"ARID2 CRISPR knockout in melanoma, mouse tumor models with anti-PD-L1 treatment, flow cytometry for CD8+ T cells, transcriptional analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined immune and transcriptional phenotype, in vivo validation, single lab\",\n      \"pmids\": [\"33333124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ARID2 haploinsufficiency is associated with enhanced RAS-MAPK (ERK1/2 phosphorylation) activity through reduced expression of IFITM1, which interacts with caveolin-1 (CAV-1) to inhibit ERK activation; demonstrated in patient iPSCs and Arid2 haploinsufficient mouse models.\",\n      \"method\": \"shRNA knockdown in HeLa cells, patient-derived iPSC neuronal differentiation, CRISPR-generated haploinsufficient mouse model, phospho-ERK western blotting, behavioral tests\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems with consistent ERK activation phenotype; pathway mechanism through IFITM1/CAV-1 partially inferred\",\n      \"pmids\": [\"33051312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARID2 mitigates hepatic steatosis by promoting ubiquitination and degradation of JAK2 via the E3 ligase NEDD4L, thereby repressing the JAK2-STAT5-PPARγ signaling axis; ARID2 recruits the methyltransferase CARM1 to the NEDD4L promoter, increasing H3R17me2a and activating NEDD4L transcription.\",\n      \"method\": \"Liver-specific Arid2 knockout mice, ChIP assay, Co-IP, ubiquitination assay, high-fat diet model, pharmacological JAK2 inhibition rescue\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP, Co-IP, ubiquitination assay, in vivo KO with pharmacological rescue; multiple orthogonal methods in single study\",\n      \"pmids\": [\"36396719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP2 deubiquitinase physically interacts with ARID2 and reduces its ubiquitin-mediated proteasomal degradation, thereby stabilizing ARID2 protein in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, CHX chase assay, ubiquitination assay\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP and ubiquitination assay, single lab\",\n      \"pmids\": [\"36567903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ARID2 and BRD4 synergistically maintain transcriptional enhancer-promoter loops at BRCA1, RAD51, and 53BP1 loci; combined ARID2 deficiency and BRD4 inhibition synergistically impairs homologous recombination and NHEJ, causing DSB accumulation and synthetic lethality in HCC cells.\",\n      \"method\": \"High-throughput drug screening, CRISPR KO, ChIP, chromosome conformation assay, DNA damage functional assays (γH2AX, RAD51 foci)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and chromatin conformation data with functional DNA repair assays, single lab\",\n      \"pmids\": [\"35017665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARID2 (Baf200) is required for hematopoietic stem cell (HSC) self-renewal and differentiation; conditional Baf200 knockout impairs long-term HSC reconstitution, erythropoiesis, and accelerates MLL-AF9-driven leukemia, with transcriptomes showing altered expression of erythropoiesis/hematopoiesis genes.\",\n      \"method\": \"Tissue-specific Cre-lox knockout (Tie2-Cre, Vav-iCre, Mx1-Cre), bone marrow transplantation, RNA-seq, leukemia mouse model\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple Cre drivers, transplantation experiments, RNA-seq, in vivo leukemia model; strong orthogonal evidence\",\n      \"pmids\": [\"29482581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HBV X protein (HBx) suppresses ARID2 transcription through downregulation of ATOH1; ATOH1 binding elements in the ARID2 promoter (nt-1040/nt-601) are required for this regulation, as mutation of ATOH1 binding sites partially abolishes HBx-triggered ARID2 repression.\",\n      \"method\": \"Reporter assays, promoter deletion analysis, ectopic ATOH1 expression, site-directed mutagenesis, Western blotting, HBV transgenic mice\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter mutagenesis with functional rescue, in vivo validation in transgenic mice; single lab\",\n      \"pmids\": [\"28498550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The ARID domain of human BAF200 (ARID2) adopts a defined secondary structure and has the potential to bind DNA sequences; NMR chemical shift assignments establish its fold as an ARID-type domain.\",\n      \"method\": \"NMR spectroscopy (backbone 1H, 13C, 15N chemical shift assignment)\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — structural assignment only, no functional validation of DNA binding specificity\",\n      \"pmids\": [\"30535613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ARID2 represses CD44 promoter activity and protein expression in HCC cells; overexpression of ARID2 inhibits migration and invasion of HepG2 and Huh7 cells and restricts subcutaneous tumor growth in nude mice.\",\n      \"method\": \"Dual luciferase reporter assay, Western blot, cell migration assay, xenograft mouse model\",\n      \"journal\": \"Zhonghua gan zang bing za zhi\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, reporter assay without ChIP validation of direct binding\",\n      \"pmids\": [\"27095763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PBAF complex (defined by ARID2) co-occupies repressive chromatin regions with PRC2 and facilitates REST transcription factor occupancy at these loci; loss of ARID2 disrupts PBAF complex integrity, impairs REST binding, and leads to upregulation of synaptic/neuronal transcripts in melanoma.\",\n      \"method\": \"ChIP-seq, ATAC-seq, CUT&RUN, ARID2 CRISPR knockout, time-resolved chromatin remodeling assays in melanoma cells and melanocytes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — comprehensive epigenomic profiling with multiple orthogonal methods; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Arid2 is required for follicular B cell differentiation and germinal center responses in vivo; Arid2 deletion impairs stage-specific gene expression programs including B cell receptor signaling, and reduces IgG antibody production after immunization.\",\n      \"method\": \"Conditional knockout mice (Mb1-Cre, CD19-Cre), bone marrow transplantation, RNA-seq of isolated B cell populations, immunization experiments, flow cytometry\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple Cre drivers with defined phenotype, transcriptomic profiling, functional immunization assay; preprint\",\n      \"pmids\": [\"41256460\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ARID2 deficiency in lung cancer impairs DNA repair and alters chromatin structure, promoting proliferation and metastasis in vitro and in vivo; ARID2 loss increases sensitivity to DNA-damaging chemotherapy agents.\",\n      \"method\": \"Targeted sequencing of patient cohort, protein expression analysis, ARID2 KO/KD functional experiments (proliferation, migration, invasion assays), in vivo tumor models, chromatin structure analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple phenotypic readouts and chromatin structural analysis; single lab\",\n      \"pmids\": [\"33742126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In TFE3-rearranged RCC, PRCC-TFE3 fusion directly binds and upregulates ERBB3 expression; ARID2 knockout further enhances this effect and activates MAPK and ERBB3 signaling pathways, with ARID2-KO cells showing heightened sensitivity to ERBB3 inhibition.\",\n      \"method\": \"ChIP assay (PRCC-TFE3 binding to ERBB3), CRISPR KO, transcriptomic analysis, in vitro/in vivo tumor models, pharmacological inhibition\",\n      \"journal\": \"Current issues in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct TFE3 binding plus ARID2 KO phenotype; pathway placed by epistasis-like pharmacological rescue\",\n      \"pmids\": [\"39727945\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARID2 is a defining subunit of the PBAF SWI/SNF chromatin-remodeling complex that selectively regulates transcription of interferon-responsive and other genes by remodeling nucleosomes at target promoters; it physically interacts with partners including E2F1 (to repress cyclin D1/E1), DNMT1 (to silence Snail via promoter methylation), RAD51 (to facilitate homology-directed DNA repair), NEDD4L/CARM1 (to ubiquitinate JAK2 and suppress JAK2-STAT5-PPARγ signaling), and REST (to maintain repressive chromatin), while also serving as a pomalidomide-induced CRL4CRBN neosubstrate whose degradation de-represses MYC in multiple myeloma; loss of ARID2 disrupts NER (via XPG misrecruitment), homologous recombination, NHEJ, and PBAF-specific REST occupancy at repressed chromatin, collectively explaining its roles as a tumor suppressor in hepatocellular carcinoma, lung adenocarcinoma, melanoma, and other cancers, as well as its essential functions in cardiac morphogenesis, hematopoiesis, and B cell differentiation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ARID2 (BAF200) is a defining subunit of the PBAF chromatin-remodeling complex that directs nucleosome remodeling at specific genomic loci to regulate transcription, DNA repair, and cell fate decisions across multiple tissues. As a PBAF specificity factor, ARID2 is required for interferon-responsive gene activation, repression of cell-cycle genes (CCND1, CCNE1) through interaction with E2F1, suppression of EMT via DNMT1 recruitment to the Snail promoter, and maintenance of REST-dependent repressive chromatin; it also activates NEDD4L transcription by recruiting CARM1, thereby promoting JAK2 ubiquitination and suppressing hepatic steatosis [PMID:15985610, PMID:27351279, PMID:32071245, PMID:36396719]. ARID2 facilitates homology-directed DNA repair through physical interaction with RAD51 and maintains nucleotide excision repair by enabling XPG recruitment to damage sites, while cooperating with BRD4 to sustain enhancer-promoter loops at DNA repair gene loci [PMID:28381560, PMID:28238438, PMID:35017665]. Loss of ARID2 causes embryonic-lethal cardiac defects, impairs hematopoietic stem cell self-renewal, and acts as a tumor suppressor in hepatocellular carcinoma, melanoma, and lung cancer; ARID2 is also a pomalidomide-induced CRL4-CRBN neosubstrate whose degradation de-represses MYC in multiple myeloma [PMID:25299188, PMID:29482581, PMID:32958952, PMID:33333124].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing ARID2 as a PBAF-specific subunit resolved how SWI/SNF subcomplexes achieve target-gene selectivity, showing that PBAF and BAF remodel distinct promoter sets and that ARID2 is required specifically for interferon-responsive gene transcription.\",\n      \"evidence\": \"Biochemical purification of PBAF/BAF, in vitro transcription assays, and RNAi-mediated gene expression profiling\",\n      \"pmids\": [\"15985610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No genome-wide binding profile for ARID2-containing PBAF\", \"Mechanism by which ARID2 confers locus selectivity undefined\", \"Whether ARID2 contributes to non-transcriptional PBAF functions unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that ARID2 knockout causes embryonic lethality with cardiac defects established ARID2 as essential for heart morphogenesis and coronary vasculogenesis, extending its role beyond transcription regulation to organ development.\",\n      \"evidence\": \"Constitutive and conditional knockout mice with histological and immunofluorescence analysis of cardiac structures\",\n      \"pmids\": [\"25299188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes mediating the cardiac phenotype not identified\", \"Whether the cardiac role is PBAF-dependent or PBAF-independent not determined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of a physical ARID2–E2F1 interaction that reduces E2F1/Pol II occupancy at CCND1 and CCNE1 promoters revealed how ARID2 directly restrains G1/S progression in hepatoma cells, linking chromatin remodeling to cell-cycle control.\",\n      \"evidence\": \"Co-immunoprecipitation, ChIP, reporter assays, and xenograft models in hepatoma cells\",\n      \"pmids\": [\"27351279\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ARID2 remodels nucleosomes at E2F1-occupied promoters or blocks E2F1 binding through steric competition is unresolved\", \"Generalizability beyond hepatoma not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that ARID2 physically interacts with RAD51 and facilitates its recruitment to DSBs, alongside identification of a BRG1-independent PBAF variant, established ARID2 as a direct participant in homology-directed DNA repair and revealed unexpected PBAF compositional heterogeneity.\",\n      \"evidence\": \"Co-IP, immunofluorescence, HR reporter assay, clonogenic survival, and biochemical fractionation\",\n      \"pmids\": [\"28381560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ARID2 promotes RAD51 loading mechanistically (chromatin remodeling vs. direct scaffolding) unclear\", \"Function of the BRG1-independent PBAF variant uncharacterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that ARID2 knockout prevents XPG accumulation at UV/carcinogen-induced damage sites linked PBAF-mediated chromatin remodeling to nucleotide excision repair and explained the hypermutation phenotype of ARID2-deficient HCC.\",\n      \"evidence\": \"CRISPR knockout in HCC cells, NER functional assay, immunofluorescence for XPG recruitment with multiple DNA-damage agents\",\n      \"pmids\": [\"28238438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID2 remodels nucleosomes at damage sites to expose DNA for XPG or acts through an indirect mechanism unknown\", \"Relationship between NER and HR roles of ARID2 not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional knockout studies in hematopoietic lineages revealed ARID2 is essential for HSC self-renewal and erythropoiesis and acts as a tumor suppressor that restrains MLL-AF9-driven leukemogenesis, broadening its developmental role to blood cell homeostasis.\",\n      \"evidence\": \"Multiple Cre-driver knockouts, bone marrow transplantation, RNA-seq, and MLL-AF9 leukemia mouse model\",\n      \"pmids\": [\"29482581\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets of ARID2 in HSCs not defined by ChIP\", \"Whether PBAF integrity is required for the hematopoietic phenotype not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of HBV core protein binding to the ARID2 C-terminus, disrupting PBAF stability and suppressing IFITM1 transcription, provided a viral mechanism for innate immune evasion through PBAF subversion.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP in multiple hepatocyte lines, transcriptional reporter assays\",\n      \"pmids\": [\"31075894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Global impact of HBc on PBAF complex composition not characterized\", \"In vivo relevance of HBc–ARID2 interaction during HBV infection not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstration that ARID2 recruits DNMT1 to the Snail promoter to methylate and silence it revealed a chromatin-remodeler–DNA-methyltransferase partnership that suppresses EMT and metastasis in HCC, with the C2H2 zinc finger domain being essential.\",\n      \"evidence\": \"Co-IP, ChIP-bisulfite sequencing, domain mutagenesis, and in vivo metastasis models\",\n      \"pmids\": [\"32071245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ARID2-DNMT1 cooperation is genome-wide or promoter-specific unknown\", \"Structural basis of the zinc finger requirement not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of ARID2 as a pomalidomide-induced CRL4-CRBN neosubstrate, degraded in a BRD7-dependent manner, uncovered a pharmacological mechanism by which immunomodulatory drugs de-repress MYC through PBAF destabilization in multiple myeloma.\",\n      \"evidence\": \"Proteomics, Co-IP, CRISPR knockout, protein stability assays, and transcriptional profiling in myeloma cells\",\n      \"pmids\": [\"32958952\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for pomalidomide-induced CRBN–ARID2 interaction not determined\", \"Whether ARID2 degradation is therapeutically beneficial or detrimental in myeloma not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Finding that ARID2 loss in melanoma upregulates STAT1 and T-cell-attracting chemokines, sensitizing tumors to anti-PD-L1 therapy, reframed ARID2 deficiency as a potential immunotherapy biomarker rather than solely a loss-of-function event.\",\n      \"evidence\": \"CRISPR knockout in melanoma, in vivo anti-PD-L1 treatment, flow cytometry, transcriptional analysis\",\n      \"pmids\": [\"33333124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAT1 upregulation is a direct consequence of altered PBAF chromatin remodeling not shown\", \"Applicability to other tumor types unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealing that ARID2 recruits CARM1 to the NEDD4L promoter to activate NEDD4L transcription, driving JAK2 ubiquitination and suppressing JAK2-STAT5-PPARγ signaling, established a chromatin-remodeler–methyltransferase–ubiquitin ligase cascade controlling hepatic lipid metabolism.\",\n      \"evidence\": \"Liver-specific Arid2 knockout mice, ChIP, Co-IP, ubiquitination assay, high-fat diet model with pharmacological JAK2 inhibition rescue\",\n      \"pmids\": [\"36396719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CARM1 recruitment requires PBAF remodeling activity not distinguished\", \"Whether this pathway operates in non-hepatic tissues unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that ARID2 and BRD4 co-maintain enhancer-promoter loops at BRCA1, RAD51, and 53BP1 loci revealed a synthetic lethal interaction exploitable therapeutically, showing ARID2 deficiency plus BRD4 inhibition catastrophically impairs both HR and NHEJ.\",\n      \"evidence\": \"High-throughput drug screening, CRISPR KO, ChIP, chromosome conformation assay, and DNA damage assays in HCC cells\",\n      \"pmids\": [\"35017665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ARID2 directly stabilizes 3D chromatin loops or acts through transcriptional regulation of loop-forming factors not resolved\", \"Applicability of synthetic lethality in clinical settings untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of USP2 as a deubiquitinase that physically interacts with and stabilizes ARID2 protein provided the first evidence of regulated ARID2 turnover outside the CRBN-dependent degradation pathway.\",\n      \"evidence\": \"Co-IP, immunofluorescence colocalization, CHX chase, and ubiquitination assays in lung cancer cells\",\n      \"pmids\": [\"36567903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The E3 ligase responsible for basal ARID2 ubiquitination not identified\", \"In vivo significance of USP2-mediated ARID2 stabilization not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis for ARID2-mediated locus selectivity within PBAF, the full complement of ARID2-dependent genomic targets across tissues, and whether ARID2's DNA-repair and transcriptional functions are mechanistically separable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of ARID2 within PBAF complex\", \"No genome-wide ChIP-seq map of ARID2 across multiple normal tissues\", \"Separation-of-function mutations distinguishing transcription from DNA repair roles not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 6, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 3, 6, 12]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3, 4, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 6, 12, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5, 10]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [3, 4, 12]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 20]}\n    ],\n    \"complexes\": [\n      \"PBAF (SWI/SNF)\",\n      \"CRL4-CRBN (as neosubstrate)\"\n    ],\n    \"partners\": [\n      \"BRG1\",\n      \"BAF180\",\n      \"BRD7\",\n      \"RAD51\",\n      \"E2F1\",\n      \"DNMT1\",\n      \"CARM1\",\n      \"USP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}