{"gene":"SMARCA4","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2001,"finding":"BRG1 (SMARCA4) fractionates into two distinct complexes that differ in activity and subunit composition; both BRG1-containing complexes and the hBrm complex can remodel nucleosomal arrays, increase restriction enzyme accessibility, and hydrolyze ATP in a DNA-dependent manner. One BRG1 complex and the hBrm complex contain mSin3A components, and BRG1, hBrm, and BAF155 directly interact with mSin3A in vitro, linking hSWI/SNF to gene repression machinery.","method":"Epitope-tagged cell lines, biochemical fractionation, nucleosome remodeling assays, ATPase assays, restriction enzyme accessibility assays, in vitro pulldown","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of enzymatic activities (ATPase, remodeling), direct pulldown interaction, multiple orthogonal methods in one study","pmids":["11238380"],"is_preprint":false},{"year":2001,"finding":"LKB1 (STK11) physically associates with BRG1, requiring the N-terminus of LKB1 and the helicase domain of BRG1. LKB1 stimulates the ATPase activity of BRG1. Expression of a kinase-dead LKB1 mutant blocks BRG1-induced growth arrest (flat-cell formation) in SW13 cells, demonstrating LKB1 kinase activity is required for BRG1-dependent growth arrest.","method":"Co-immunoprecipitation, domain-mapping pulldown, ATPase activity assay, cell-based growth arrest assay with kinase-dead mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical ATPase assay plus domain-mapped co-IP plus functional epistasis in cell-based system, single lab with multiple orthogonal methods","pmids":["11445556"],"is_preprint":false},{"year":2004,"finding":"BRG1 reintroduction into BRG1-mutant breast tumor cells induces growth arrest accompanied by upregulation of CDK inhibitors p21 and p15; p21 protein is recruited to a complex with CDK2 to inhibit its activity. BRG1 associates with the p21 promoter in a p53-independent manner, suggesting direct transcriptional activation of p21.","method":"BRG1 re-expression in BRG1-null cells, microarray/RT-PCR, protein co-immunoprecipitation (p21-CDK2 complex), chromatin immunoprecipitation (ChIP)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing BRG1 at p21 promoter plus co-IP of p21-CDK2 complex plus functional rescue, single lab","pmids":["14673169"],"is_preprint":false},{"year":2004,"finding":"STAT3 recruits BRG1 to the p21waf1 promoter upon cytokine stimulation; BRG1 loading results in increased chromatin accessibility at the proximal p21waf1 promoter and association of RNA Polymerase II, establishing BRG1 as a downstream effector of STAT3-mediated chromatin remodeling and transcription initiation.","method":"Co-immunoprecipitation, pulldown, chromatin immunoprecipitation (ChIP), Southern blot restriction enzyme accessibility assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus ChIP plus chromatin accessibility assay, single lab with multiple orthogonal methods","pmids":["15286705"],"is_preprint":false},{"year":2006,"finding":"BRG1 disrupts a positioned nucleosome at the TG-repeat sequence in the CSF1 promoter and induces Z-DNA formation. Both BRG1 remodeling activity and Z-DNA formation are required cooperatively for effective chromatin remodeling of the CSF1 promoter; active transcription expands but is not required to initiate Z-DNA formation.","method":"Nucleosome positioning assays, chromatin remodeling assays, Z-DNA antibody immunoprecipitation, restriction enzyme accessibility, transcription inhibition experiments","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple chromatin assays in single lab demonstrating cooperative mechanism, no independent replication","pmids":["16537901"],"is_preprint":false},{"year":2013,"finding":"BRG1 promotes COUP-TFII expression in venous endothelial cells during murine embryogenesis by binding conserved regulatory elements within the COUP-TFII promoter and remodeling chromatin to increase promoter accessibility, thereby governing venous specification. Conditional endothelial deletion of Brg1 results in downregulated COUP-TFII and aberrant arterial marker expression on veins.","method":"Conditional knockout mouse model, ChIP, chromatin accessibility assay, immunofluorescence","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at COUP-TFII promoter plus conditional KO with defined vascular phenotype, single lab","pmids":["23406903"],"is_preprint":false},{"year":2015,"finding":"BRG1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at enhancers activated during mesoderm induction. BRG1 is also required to maintain Polycomb-mediated H3K27me3 repression at non-mesodermal developmental regulators, demonstrating a dual role in activating lineage-specific enhancers and maintaining repression of alternative lineage genes.","method":"ESC-based directed differentiation, Brg1 conditional knockout, ChIP-seq for H3K27ac and H3K27me3, gene expression analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with conditional KO in defined differentiation system, single lab","pmids":["25813539"],"is_preprint":false},{"year":2015,"finding":"Evf2 lncRNA is present in a ribonucleoprotein complex with BRG1 (SMARCA4) and BAF170 (SMARCC2) in the developing mouse forebrain. Evf2 RNA directly inhibits BRG1 ATPase and chromatin remodeling activities in vitro. BRG1 interacts with DLX1 and Evf2 through distinct binding sites. RNA-mediated inhibition of BRG1 ATPase/remodeling is promiscuous in vitro. Coffin-Siris syndrome mutations localize to the BRG1 RNA-binding and DLX1-binding domains.","method":"Mass spectrometry, co-immunoprecipitation, in vitro ATPase assay, in vitro remodeling assay, nuclear colocalization imaging","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ATPase inhibition assay plus in vitro remodeling assay plus MS identification of complex plus co-IP, single lab with multiple orthogonal methods","pmids":["26138476"],"is_preprint":false},{"year":2015,"finding":"Brg1 controls chromatin remodeling and transcriptional activation at the Pax7 promoter in muscle satellite cells, and is required for viability and proliferation of primary myoblasts. Loss of Brg1 causes apoptosis; reintroduction of catalytically active Brg1 or Pax7 rescues the apoptotic phenotype.","method":"Conditional Brg1 deletion in primary satellite cells, ChIP, apoptosis assays, rescue with active Brg1 vs. Pax7","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at Pax7 promoter plus conditional KO phenotype plus catalytically active rescue, single lab","pmids":["26036967"],"is_preprint":false},{"year":2015,"finding":"BRG1 is required for glucocorticoid receptor (GR)-mediated transcription. BRG1 pre-occupies GR binding sites (GBSs) prior to hormone exposure and is required for recruitment of pioneer factors FOXA1 and GATA3 to GBSs. GR interaction with FOXA1 and GATA3 binding sites was restricted to sites pre-bound by BRG1.","method":"BRG1 knockdown in human breast cancer cells, ChIP-seq for BRG1/GR/FOXA1/GATA3, transcriptional activation assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with BRG1 knockdown plus pioneer factor recruitment data, single lab","pmids":["29792595"],"is_preprint":false},{"year":2015,"finding":"Ku70 (XRCC6) associates with a BRG1 fragment encompassing the HSA and BRK domains. Ku70/86 and components of the TOP2β/PARP1 complex are required for NR-mediated SWI/SNF-dependent transcriptional activation from endogenous promoters. GR/BRG1-dependent TOP2β-mediated transient double-strand DNA breaks are required for efficient GR-stimulated transcription.","method":"BRG1 domain-fragment pulldown, ChIP, transcriptional activation assay, TOP2β inhibition experiments","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped pulldown plus ChIP plus functional transcription assays, single lab","pmids":["26055322"],"is_preprint":false},{"year":2017,"finding":"SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of chromatin remodeling. Heterozygous expression of dominant-negative SMARCA4 mutants alters the open chromatin landscape at thousands of sites, causing loss of DNA accessibility at active enhancers (H3K27ac loss, H3K4me1 retained) and inducing pro-oncogenic expression changes including increased MYC expression.","method":"ATPase mechanochemical analysis, ATAC-seq, ChIP-seq (H3K27ac, H3K4me1), Polycomb ChIP-seq, gene expression analysis in cells expressing dominant-negative mutants","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mechanochemical cycle disruption demonstrated plus ATAC-seq plus ChIP-seq across multiple chromatin marks, comprehensive mechanistic study","pmids":["29323272"],"is_preprint":false},{"year":2017,"finding":"BRG1 bromodomain (BRD) has moderate specificity for H3K14ac. Both BRG1 and hBRM BRDs have DNA-binding activity through a surface basic patch; the BRD and an adjacent AT-hook make multivalent contacts with DNA showing affinity for AT-rich elements. Histone-binding activity does not substantially contribute to nucleosome targeting in vitro, and neither BRD histone nor DNA binding contribute to global chromatin affinity of BRG1 in mouse ESCs.","method":"Biochemical binding assays, NMR, SELEX, mutagenesis of basic patch, in vitro nucleosome binding assays, mouse ESC chromatin binding","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural characterization plus mutagenesis plus in vitro binding assays plus cellular validation, single lab with multiple orthogonal methods","pmids":["28706277"],"is_preprint":false},{"year":2017,"finding":"BRG1 knockdown globally alters long-range genomic interactions and reduces TAD boundary strength, suggesting BRG1 affects nucleosome occupancy around CTCF sites at TAD boundaries and may regulate CTCF and topoisomerase complex recruitment.","method":"BRG1 knockdown, Hi-C/genome organization analysis, CTCF ChIP","journal":"Nucleus (Austin, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, knockdown with genome organization data, primarily review/commentary with limited new experimental data reported in abstract","pmids":["28060558"],"is_preprint":false},{"year":2018,"finding":"SCFFBW7 ubiquitin ligase mediates BRG1 protein degradation. CK1δ phosphorylates BRG1 at Ser31/Ser35 residues to facilitate BRG1 binding to FBW7, leading to ubiquitination-mediated degradation. Stabilization of BRG1 in gastric cancer cells suppresses E-cadherin expression and promotes metastasis.","method":"Co-immunoprecipitation, site-directed mutagenesis (Ser31/Ser35), ubiquitination assay, kinase assay, E-cadherin expression analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phosphorylation site mutagenesis plus ubiquitination assay plus co-IP plus functional downstream readout, single lab with multiple orthogonal methods","pmids":["30177679"],"is_preprint":false},{"year":2018,"finding":"HDAC3 inhibition by entinostat decreases SMARCA4 chromatin remodeling activity, which in turn derepresses miR-27a, leading to destabilization of PAX3:FOXO1 mRNA and chemotherapy sensitization in alveolar rhabdomyosarcoma cells.","method":"HDAC3 inhibition, SMARCA4 activity assays, miR-27a expression analysis, mRNA stability assays, in vivo mouse models","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pathway epistasis with multiple cellular and in vivo readouts, single lab","pmids":["30459282"],"is_preprint":false},{"year":2019,"finding":"Xist lncRNA directly interacts with BRG1, and in vitro RNA binding inhibits nucleosome-remodeling and ATPase activities of BRG1. In cells, Xist expels BRG1 from the inactive X chromosome; Xist deletion allows selective return of BRG1 in cis, which correlates with cohesin binding and restoration of TADs and formation of de novo 'superloops'.","method":"In vitro ATPase assay, in vitro nucleosome remodeling assay, RNA-protein interaction assay, ChIP-seq, ATAC-seq, Hi-C, Xist deletion cell system","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ATPase inhibition plus in vitro remodeling assay plus genomic ChIP-seq plus structural domain analysis, single lab with multiple orthogonal methods","pmids":["30664740"],"is_preprint":false},{"year":2019,"finding":"PTEN loss stabilizes BRG1 protein through inhibition of the AKT/GSK3β/FBXW7 axis. Increased BRG1 in PTEN-deficient prostate cancer cells drives chromatin remodeling into a protumorigenic transcriptome, creating a synthetic lethal dependency on BRG1.","method":"Genetically engineered mouse models, organoid assays, protein stability analysis, co-immunoprecipitation, ChIP, BRG1 inhibitor treatment","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GEM and organoid models plus ChIP plus protein stabilization mechanism, single lab","pmids":["30496141"],"is_preprint":false},{"year":2019,"finding":"BRG1 interacts with KDM3A histone demethylase on the MUC1 promoter in a STAT1- and RelA-dependent manner, demethylating H3K9 to activate MUC1 transcription in breast cancer cells.","method":"ChIP, co-immunoprecipitation, siRNA knockdown of BRG1/KDM3A, histone modification analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — co-IP plus ChIP plus KD rescue, single lab single study","pmids":["30824191"],"is_preprint":false},{"year":2019,"finding":"BRG1 interacts with RORγ and is recruited to the Elovl3 promoter; BRG1 also interacts with histone acetyltransferase p300 to activate Elovl3 transcription in response to androgen and TGF-β in prostate cancer cells.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, gene expression analysis","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP plus ChIP, single lab, limited mechanistic validation","pmids":["31154107"],"is_preprint":false},{"year":2020,"finding":"BRG1 (SMARCA4)-containing SWI/SNF complexes physically interact with RPA complexes, as shown by quantitative mass spectrometry and co-immunoprecipitation. BRG1 loss in lung cancer cells leads to increased origin firing mediated by CDC6 and activation of replication stress responses, creating dependency on ATR kinase.","method":"Co-immunoprecipitation, quantitative mass spectrometry, single-molecule replication fork dynamics (DNA fiber assay), pharmacological ATR inhibition","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with MS plus single-molecule replication assay plus functional ATR dependency, single lab","pmids":["32690724"],"is_preprint":false},{"year":2020,"finding":"Acute depletion of BRG1 (via auxin-inducible degron in knock-in mice) leads to decreased nascent RNA production and RNA Polymerase II binding at many genes, correlated with loss of BRG1 occupancy, diminished chromatin accessibility at DHSs, decreased p300 binding, and narrower nucleosome spacing at TF motifs, enhancers, and TSSs. Acute BRG1 depletion also severely compromises TSA-induced histone acetylation.","method":"Auxin-inducible degron knock-in mouse, SLAM-seq (nascent RNA), ChIP-seq (RNAPII, BRG1, p300), ATAC-seq, nucleosome mapping","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — acute depletion system (AID tag in mice) plus multiple orthogonal genome-wide methods (nascent RNA, ChIP-seq, ATAC-seq, nucleosome mapping) across multiple cell types","pmids":["38811575"],"is_preprint":false},{"year":2020,"finding":"CK2 (casein kinase 2) interacts with Brg1 and phosphorylates it in a mitotic-specific manner (hyperphosphorylation during mitosis). CK2-mediated phosphorylation is associated with partitioning of Brg1 to soluble chromatin during mitosis, and this phosphorylation pattern is conserved across multiple cell types and organisms.","method":"Co-immunoprecipitation, phosphorylation/kinase assays, subcellular fractionation, cell-cycle synchronization, immunofluorescence in embryonic somites and primary myoblasts","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation plus kinase assay plus co-IP plus subcellular localization across multiple cell types, single lab","pmids":["32019271"],"is_preprint":false},{"year":2021,"finding":"PRMT1-mediated H4R3me2a histone modification directly recruits SMARCA4 to chromatin. SMARCA4 and PRMT1 cooperatively promote CRC progression by activating EGFR and TNS4 transcription. The SMARCA4 R1157W mutation enhances recruitment to H4R3me2a and increases SWI/SNF ATPase activity.","method":"Co-immunoprecipitation, ChIP-seq, ChIP, cell viability/migration assays, in vivo mouse CRC model, ATPase activity assay for R1157W mutant","journal":"Genome medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing H4R3me2a-dependent SMARCA4 recruitment plus functional knockdown assays plus in vivo model, single lab","pmids":["33853662"],"is_preprint":false},{"year":2021,"finding":"Smarca4 loss impairs the function of all three classes of SWI/SNF complexes (BAF, PBAF, GBAF), resulting in decreased chromatin accessibility at lung lineage transcription factor motifs, ultimately driving dedifferentiated tumor states and accelerated metastasis in a cell-type-dependent manner.","method":"Conditional Smarca4 knockout mouse lung cancer model, ATAC-seq, scRNA-seq, chromatin accessibility analysis, SWI/SNF complex immunoprecipitation","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO plus ATAC-seq plus SWI/SNF complex function analysis across all three complex types, single lab comprehensive study","pmids":["34561242"],"is_preprint":false},{"year":2021,"finding":"KDM2B interacts with Brg1 (the SWI/SNF ATPase subunit) to facilitate chromatin accessibility at the Il6 promoter specifically, and this interaction is required for IL-6 induction in macrophages/dendritic cells without altering histone demethylation at the locus.","method":"Co-immunoprecipitation, ChIP, KDM2B-conditional knockout mice, ATAC/chromatin accessibility assay","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP plus conditional KO with specific cytokine phenotype, single lab","pmids":["31197256"],"is_preprint":false},{"year":2021,"finding":"Brg1 is required for NKp46+ ILC3 differentiation by promoting T-bet expression. Brg1 binds to both the Tbx21 and Csf2 gene loci in ILC3s, promoting active histone modifications at Tbx21 (activating T-bet) and repressive modifications at Csf2 (suppressing GM-CSF), through a cell-intrinsic mechanism that restrains intestinal inflammation.","method":"ILC3-specific Brg1 conditional KO, mixed bone marrow chimera, flow cytometry, ChIP for histone modifications at Tbx21 and Csf2 loci","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO plus ChIP for histone marks plus cell-intrinsic chimera experiment, single lab","pmids":["32612160"],"is_preprint":false},{"year":2021,"finding":"Neuronal activity induces BRG1 phosphorylation at a serine residue sensitive to CaMKII inhibition. Phosphorylation alters BRG1 interaction with the NuRD repressor complex and cohesin, modulating enhancer-promoter looping, RNA Pol II recruitment, and enhancer RNA expression. Non-phosphorylatable BRG1 knockin mice fail to efficiently induce activity-dependent genes and show anxiety-like phenotypes.","method":"CaMKII inhibition, BRG1 phosphorylation mapping, co-immunoprecipitation (NuRD, cohesin), ChIP-seq, enhancer RNA quantification, knockin mouse behavior phenotyping","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-site-specific knockin mice plus ChIP-seq plus co-IP demonstrating changed interactions, single lab","pmids":["34260936"],"is_preprint":false},{"year":2021,"finding":"SMARCA4 loss renders lung cancer cells and primary SCCOHT cells highly sensitive to inhibition of KDM6A/UTX and KDM6B/JMJD3 histone demethylases. SMARCA4-mutant cells show impaired transactivation, aberrant H3K27me3 accumulation, and significantly reduced KDM6A/KDM6B levels compared to SMARCA4-intact cells.","method":"SMARCA4-mutant cell lines, KDM6 inhibitor (GSK-J4) treatment, in vivo orthotopic tumor models, H3K27me3 ChIP, gene expression analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link between SMARCA4 loss and H3K27me3 accumulation plus in vivo validation, single lab","pmids":["34262032"],"is_preprint":false},{"year":2021,"finding":"OTUD6A deubiquitinase stabilizes BRG1 by erasing K27-linked polyubiquitination, thereby preventing its degradation in prostate cancer cells. OTUD6A catalytic activity (not dead-mutant) is required for this stabilization and for prostate cancer cell progression.","method":"Mass spectrometry substrate screening, co-immunoprecipitation, ubiquitination assay, catalytic dead mutant, in vivo PDX and GEM models","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification plus ubiquitination assay plus catalytic mutant plus in vivo models, single lab","pmids":["35233061"],"is_preprint":false},{"year":2022,"finding":"SMARCA4/2 loss represses GLUT1 expression, reduces glucose uptake and glycolysis, and increases dependency on oxidative phosphorylation fueled by elevated glutamine import via SLC38A2. SMARCA4/2-deficient cells are sensitive to OXPHOS inhibitors and glutamine metabolism inhibitors; alanine supplementation competes with glutamine uptake via SLC38A2 and selectively kills SMARCA4/2-deficient cells.","method":"SMARCA4/2 double-knockout cells, metabolic flux assays, glucose uptake assays, SLC38A2 knockdown, in vitro and patient-derived xenograft treatment experiments","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — metabolic mechanism defined with multiple functional assays and PDX validation, single lab","pmids":["37210563"],"is_preprint":false},{"year":2022,"finding":"Hemogen recruits SWI/SNF complex ATPase BRG1 as a coactivator to regulate nucleosome accessibility and H3K27ac enrichment at erythroid gene promoters and enhancers. BRG1 is largely dependent on hemogen to regulate chromatin accessibility at erythroid gene promoters/enhancers in mouse fetal liver, as shown by hemogen-knockout animals.","method":"Co-immunoprecipitation, ChIP-seq in WT and hemogen-KO mice, ATAC-seq, hemogen-knockout/knockin mouse models","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq in KO animals plus co-IP plus ATAC-seq, single lab with in vivo KO validation","pmids":["35297980"],"is_preprint":false},{"year":2022,"finding":"Brg1 loss leads to immediate increased tolerance to aneuploidy in chromosomally stable cells, and fitness recovery over time correlates with chromosome gain, demonstrating BRG1 normally suppresses aneuploidy tolerance.","method":"BRG1 deletion in chromosomally stable cell line, karyotype analysis, fitness/proliferation assays over time, proteomics","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct BRG1 deletion with karyotypic and fitness tracking, single lab","pmids":["35365638"],"is_preprint":false},{"year":2022,"finding":"SMARCA4 colocalizes with SOX10 at gene regulatory elements in diffuse midline glioma (DMG) cells; SMARCA4 chromatin binding is reduced upon depletion of SOX10 or H3.3K27M mutation. SMARCA4 controls expression of genes involved in cell growth and the extracellular matrix in DMG.","method":"ChIP-seq for SMARCA4 and SOX10, SMARCA4 KO/knockdown, H3.3K27M depletion, gene expression analysis, patient-derived xenograft models","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq showing co-occupancy plus conditional depletion experiments, single lab","pmids":["36305747"],"is_preprint":false},{"year":2023,"finding":"Brg1 interacts with lysine demethylase Kdm7aa in cardiac endothelial cells; this complex fine-tunes H3K4me3 at the promoter regions of Notch family genes, modulating Notch transcription during zebrafish heart regeneration. Dominant-negative Brg1 expression in endothelium causes abnormal Notch activation and inhibits myocardial regeneration.","method":"Co-immunoprecipitation, ChIP-seq (H3K4me3), RNA-seq, endothelium-specific dominant-negative Brg1 overexpression in zebrafish","journal":"NPJ Regenerative medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus co-IP plus in vivo zebrafish genetic model, single lab","pmids":["37029137"],"is_preprint":false},{"year":2023,"finding":"Brg1 directly binds to the CXCL14 promoter and activates its transcription in hepatocytes, driving neutrophil trafficking during alcoholic liver disease. Pharmaceutical inhibition of Brg1 with PFI-3 reduces CXCL14 expression and alleviates ALD pathogenesis.","method":"Hepatocyte-specific Brg1 manipulation, RNA-seq, ChIP at CXCL14 promoter, flow cytometry, PFI-3 small molecule inhibitor treatment, in vivo ALD mouse models","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at target promoter plus conditional KO with specific flow cytometric phenotype plus pharmacological validation, single lab","pmids":["36722664"],"is_preprint":false},{"year":2023,"finding":"The SMARCA4 R1157W mutation facilitates recruitment to PRMT1-mediated H4R3me2a chromatin and enhances the ATPase activity of the SWI/SNF complex, reinforcing transcriptional activation of EGFR and TNS4 to promote CRC cell proliferation.","method":"SMARCA4 R1157W mutant expression, ATPase activity assay, ChIP, organoid proliferation assays, xenograft models, PRMT1/SMARCA4 inhibitor combination","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ATPase assay for mutant plus ChIP plus organoid/in vivo models, single lab","pmids":["36922568"],"is_preprint":false},{"year":2023,"finding":"Brg1 controls stemness and metastasis of pancreatic ductal adenocarcinoma through regulation of the hypoxia pathway. Brg1 is required for HIF-1α to bind its target genes, augmenting the hypoxia transcriptional program that maintains cancer stem-like properties and enables liver metastasis.","method":"Dual recombinase conditional Brg1 deletion in established PDAC, splenic injection/peritoneal dissemination metastasis models, ChIP for HIF-1α binding, gene expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO in established tumors plus ChIP for HIF-1α at target genes plus metastasis models, single lab","pmids":["37198398"],"is_preprint":false},{"year":2024,"finding":"SMARCA4 loss in ovarian cancer models results in up-regulation of long-terminal RNA repeats, increased expression of interferon-stimulated genes, and up-regulation of antigen presentation machinery, dependent on STING, MAVS, and IRF3 signaling but independent of type I interferon receptor. Mouse tumors with SMARCA4 loss show increased cytotoxic T cell, NK cell, and myeloid infiltration.","method":"SMARCA4 knockout in ovarian cancer cells, RNA-seq, STING/MAVS/IRF3 knockdown epistasis, immune cell flow cytometry in mouse tumor models, BRG1 inhibitor treatment of SMARCA4-proficient cells","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple pathway components plus in vivo immune phenotyping plus pharmacological validation, single lab","pmids":["39630912"],"is_preprint":false},{"year":2024,"finding":"The BRG1 AT-hook of the esBAF complex preferentially binds RNA and associates with eRNA transcribed from intronic and intergenic regions. SWI/SNF is globally recruited in cis by eRNA to cell-type-specific enhancers; this facilitates recruitment of MLL3/4, p300/CBP, and Mediator to stage-specific enhancers and super-enhancers.","method":"RNA binding assays (AT-hook), eRNA co-immunoprecipitation, ChIP-seq for BRG1/MLL3/4/p300/Mediator at enhancers, cell lineage differentiation stages","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA binding assay plus ChIP-seq across differentiation stages plus coactivator co-occupancy, single lab","pmids":["38593804"],"is_preprint":false},{"year":2020,"finding":"NMR spectroscopy and molecular modelling of the BRG1 AT-hook/bromodomain composite domain reveal the structural basis of DNA specificity. SELEX-seq identified preferred DNA sequences for this domain; cancer mutations in the DNA-binding pocket alter the mode of DNA association.","method":"NMR spectroscopy, SELEX-seq, molecular modelling, mutagenesis of cancer-associated residues","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structural determination plus SELEX-seq plus mutagenesis of cancer mutations, single lab with multiple orthogonal Tier 1 methods","pmids":["32376391"],"is_preprint":false},{"year":2018,"finding":"BRG1 binds to the Sox9 promoter in pancreatic acinar cells to regulate Sox9 expression and is critical for recruitment of upstream regulators PDX1 to the Sox9 promoter and enhancer. BRG1 loss blocks acinar-to-ductal metaplasia (ADM) and PanIN formation; Sox9 overexpression rescues the PanIN-attenuated phenotype of BRG1-deficient mice.","method":"Acinar-specific Brg1 conditional KO in Kras-mutant mice, ChIP at Sox9 promoter/enhancer, Sox9 overexpression rescue experiment, dual recombinase system for established PanIN deletion","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at Sox9 regulatory elements plus conditional KO plus genetic rescue (Sox9 overexpression) plus dual recombinase regression experiment, comprehensive single-lab study","pmids":["30010625"],"is_preprint":false},{"year":2017,"finding":"BRG1/BRM repress c-Myc expression in adult cardiomyocytes; loss of both BRG1 and BRM leads to upregulated c-MYC and progressive ventricular dysfunction with conduction defects. BRG1/BRM and c-MYC have opposite effects on cardiac conduction gene expression; BRG1/BRM occupancy is diminished at target genes in human heart failure cases.","method":"Tamoxifen-inducible cardiomyocyte-specific Brg1/Brm double KO, echocardiography, electrocardiography, inducible c-MYC overexpression, ChIP in human heart failure specimens","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional double KO with functional cardiac phenotype plus ChIP in human samples plus genetic epistasis with c-MYC, single lab","pmids":["28232072"],"is_preprint":false},{"year":2018,"finding":"SMARCAL1 and BRG1 co-localize on the promoters of ATM and ATR; downregulation of both results in transcriptional repression of ATM/ATR and override of the G2/M checkpoint. On DNA damage, phospho-ATM binds to the promoters of SMARCAL1, BRG1, ATM, and ATR, creating a feedback regulatory loop.","method":"ChIP (SMARCAL1, BRG1 at ATM/ATR promoters), siRNA knockdown, cell cycle checkpoint assays, phospho-ATM ChIP","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP co-localization plus knockdown epistasis plus phospho-ATM feedback ChIP, single lab","pmids":["30317028"],"is_preprint":false}],"current_model":"SMARCA4/BRG1 is the catalytic ATPase subunit of mammalian SWI/SNF (BAF/PBAF/GBAF) chromatin remodeling complexes that uses ATP hydrolysis to reposition nucleosomes, increase chromatin accessibility at enhancers and promoters, and thereby activate or repress transcription; its chromatin binding, enzymatic activity, and protein stability are regulated by post-translational modifications including CK1δ/CK2-mediated phosphorylation (governing FBW7-mediated ubiquitin degradation), OTUD6A-mediated deubiquitination, CaMKII-induced neuronal activity-dependent phosphorylation, and recognition of the histone mark H4R3me2a; it is recruited to target loci through interactions with transcription factors (STAT3, GR, RORγ, SOX10, hemogen, NF-κB/RelA) and through its AT-hook/bromodomain binding to DNA and eRNA, and its activity can be inhibited by noncoding RNAs (Xist, Evf2); loss of SMARCA4 impairs all three SWI/SNF complex classes, reduces chromatin accessibility at lineage-specific enhancers, causes replication stress via CDC6-dependent origin firing and RPA complex uncoupling, and triggers STING/MAVS/IRF3-dependent innate immune signaling."},"narrative":{"mechanistic_narrative":"SMARCA4/BRG1 is the catalytic ATPase subunit of mammalian SWI/SNF (BAF/PBAF/GBAF) chromatin-remodeling complexes that hydrolyzes ATP to reposition nucleosomes and set chromatin accessibility at enhancers, promoters, and lineage-specific regulatory elements, with its loss impairing all three complex classes and collapsing accessibility at lineage transcription-factor motifs [PMID:11238380, PMID:34561242]. Acute degron-based depletion establishes BRG1 as a direct positive driver of transcription: it maintains chromatin accessibility at DNase-hypersensitive sites, nucleosome spacing at TF motifs, p300 recruitment, histone acetylation, and RNA Pol II loading at active loci [PMID:38811575]. Genome-wide it co-localizes with H3K27ac at distal enhancers to support their activation while simultaneously maintaining Polycomb H3K27me3 repression of alternative-lineage genes, a dual activating/repressive function [PMID:25813539, PMID:29323272]. BRG1 is targeted to chromatin by a multivalent AT-hook/bromodomain composite domain that preferentially binds AT-rich DNA and RNA, including enhancer RNAs that recruit SWI/SNF in cis to cell-type-specific enhancers and license MLL3/4, p300/CBP, and Mediator loading [PMID:28706277, PMID:32376391, PMID:38593804], and by recognition of PRMT1-deposited H4R3me2a [PMID:33853662]. Locus specificity is conferred through interactions with transcription factors and cofactors including STAT3, glucocorticoid receptor (with FOXA1/GATA3 pioneer recruitment), SOX10, hemogen, HIF-1α, and PDX1/SOX9 [PMID:15286705, PMID:29792595, PMID:36305747, PMID:35297980, PMID:37198398, PMID:30010625]. Its abundance is controlled by a phospho-degron axis in which CK1δ phosphorylation of Ser31/Ser35 promotes FBW7-mediated ubiquitination and degradation, opposed by OTUD6A deubiquitination, while CaMKII-dependent activity-induced phosphorylation rewires its association with NuRD and cohesin to modulate enhancer-promoter looping [PMID:30177679, PMID:35233061, PMID:34260936]. BRG1 ATPase and remodeling activities are directly inhibited in vitro by noncoding RNAs Xist and Evf2, with Xist expelling BRG1 from the inactive X to reorganize TADs [PMID:26138476, PMID:30664740]. Cancer missense mutations target the ATPase mechanochemical cycle to act dominant-negatively and reshape the accessible chromatin landscape toward pro-oncogenic programs such as MYC induction [PMID:29323272]. SMARCA4 loss additionally provokes CDC6-dependent origin firing, uncoupling from RPA complexes and ATR-dependent replication stress, and derepresses long-terminal repeats to trigger STING/MAVS/IRF3-dependent innate immune signaling [PMID:32690724, PMID:39630912]. Coffin-Siris syndrome mutations map to its RNA- and DLX1-binding domains [PMID:26138476].","teleology":[{"year":2001,"claim":"Established BRG1 as a bona fide ATP-dependent nucleosome-remodeling enzyme that exists in distinct multi-subunit complexes and physically links to repressive machinery, defining its core biochemical activity.","evidence":"Biochemical fractionation, in vitro nucleosome remodeling and ATPase assays, and in vitro pulldown with mSin3A components in tagged cell lines","pmids":["11238380"],"confidence":"High","gaps":["Did not resolve how distinct complexes select different genomic targets","Repressive vs activating mode at endogenous loci not defined"]},{"year":2001,"claim":"Showed BRG1 ATPase activity is stimulated by an upstream kinase (LKB1) whose catalytic activity is required for BRG1-driven growth arrest, connecting remodeling to tumor-suppressor signaling.","evidence":"Domain-mapped co-IP, ATPase assay, and kinase-dead epistasis in SW13 growth-arrest assay","pmids":["11445556"],"confidence":"High","gaps":["Phosphorylation sites on BRG1 by LKB1 not mapped","Mechanism of ATPase stimulation unresolved"]},{"year":2004,"claim":"Identified BRG1 as a transcription-factor-recruited remodeler at the p21 promoter, showing STAT3 brings BRG1 to open chromatin and load RNA Pol II, framing it as a downstream effector of signaling pathways.","evidence":"BRG1 re-expression, co-IP, ChIP, and restriction-enzyme accessibility assays in tumor cells","pmids":["14673169","15286705"],"confidence":"Medium","gaps":["p53-independence of p21 activation not fully resolved","Generalizability of TF-directed recruitment beyond p21 untested at the time"]},{"year":2006,"claim":"Demonstrated BRG1 remodeling can drive non-B DNA structural transitions (Z-DNA) cooperatively required for promoter remodeling, expanding its mechanism beyond simple nucleosome sliding.","evidence":"Nucleosome positioning, Z-DNA immunoprecipitation, and transcription-inhibition assays at the CSF1 promoter","pmids":["16537901"],"confidence":"Medium","gaps":["Single-promoter observation","Generality of Z-DNA coupling across BRG1 targets unknown"]},{"year":2015,"claim":"Established BRG1 as a lineage-determining remodeler in vivo, activating tissue-specific enhancers and gene programs (COUP-TFII, Pax7, mesodermal enhancers) while also maintaining Polycomb repression of alternative lineages.","evidence":"Conditional Brg1 knockouts, ChIP/ChIP-seq for H3K27ac and H3K27me3, and rescue experiments in endothelium, satellite cells, and ESC differentiation","pmids":["23406903","26036967","25813539"],"confidence":"Medium","gaps":["How BRG1 sustains repressive H3K27me3 mechanistically unresolved","Direct vs indirect enhancer effects not fully separated"]},{"year":2015,"claim":"Revealed BRG1 cooperates with glucocorticoid receptor and DNA-break machinery, pre-marking GR binding sites and enabling pioneer-factor recruitment and TOP2β-mediated transient double-strand breaks for transcription.","evidence":"BRG1 knockdown with ChIP-seq for GR/FOXA1/GATA3, domain pulldown of Ku70, and TOP2β inhibition transcription assays","pmids":["29792595","26055322"],"confidence":"Medium","gaps":["How BRG1 selects GR sites prior to hormone unknown","Physiological role of break formation vs collateral damage unresolved"]},{"year":2015,"claim":"Defined noncoding RNAs as direct inhibitors of BRG1 enzymatic activity, with Evf2 and later Xist binding and suppressing ATPase/remodeling, and Xist expelling BRG1 to reorganize X-chromosome TADs.","evidence":"MS, co-IP, in vitro ATPase and remodeling assays, and Hi-C/ChIP-seq in Xist-deletion cells","pmids":["26138476","30664740"],"confidence":"High","gaps":["In vitro RNA inhibition is promiscuous; specificity in vivo unclear","Whether eRNA stimulation and lncRNA inhibition share a binding mode unresolved"]},{"year":2017,"claim":"Mapped the structural basis of BRG1 chromatin targeting, showing the AT-hook/bromodomain composite preferentially binds AT-rich DNA over histone marks, with cancer mutations altering DNA association.","evidence":"NMR, SELEX-seq, mutagenesis of the basic patch, and in vitro/ESC binding assays","pmids":["28706277","32376391"],"confidence":"High","gaps":["Contribution of DNA binding to global targeting found minor; the dominant targeting determinant left open","RNA-binding role of this domain not yet defined at this stage"]},{"year":2017,"claim":"Established that cancer-associated ATPase mutations act dominant-negatively to disrupt the remodeling mechanochemical cycle and reshape the accessible chromatin landscape toward pro-oncogenic output including MYC.","evidence":"Mechanochemical analysis, ATAC-seq, and multi-mark ChIP-seq in cells expressing dominant-negative mutants","pmids":["29323272"],"confidence":"High","gaps":["How specific loci are selectively lost vs retained unresolved","Link between accessibility loss and MYC induction not fully mechanistic"]},{"year":2018,"claim":"Defined a phospho-degron controlling BRG1 abundance, with CK1δ phosphorylating Ser31/Ser35 to drive SCF-FBW7 ubiquitination and degradation, coupling protein turnover to oncogenic phenotypes.","evidence":"Site-directed mutagenesis, ubiquitination and kinase assays, and co-IP with downstream E-cadherin readout","pmids":["30177679"],"confidence":"High","gaps":["Upstream signals controlling CK1δ phosphorylation unresolved","Whether degradation is cell-cycle or context restricted unclear"]},{"year":2019,"claim":"Extended BRG1 abundance control upstream and reciprocally, with PTEN loss stabilizing BRG1 via the AKT/GSK3β/FBXW7 axis and OTUD6A deubiquitinase removing K27-linked chains to prevent degradation, both creating BRG1 dependencies in cancer.","evidence":"GEM and organoid/PDX models, protein-stability and ubiquitination assays, and catalytic-dead OTUD6A controls","pmids":["30496141","35233061"],"confidence":"Medium","gaps":["Interplay between OTUD6A and FBW7 not co-defined","Direct E3 vs DUB balance in normal cells unquantified"]},{"year":2021,"claim":"Identified histone-mark- and signaling-directed recruitment of SMARCA4, including PRMT1-deposited H4R3me2a recruitment and CaMKII-dependent activity-induced phosphorylation that rewires NuRD/cohesin interactions and enhancer looping.","evidence":"ChIP-seq, co-IP, ATPase assays for the R1157W mutant, and phospho-site knockin mice with behavioral and eRNA readouts","pmids":["33853662","34260936"],"confidence":"Medium","gaps":["The CaMKII-targeted phosphosite not definitively mapped","How H4R3me2a recruitment integrates with TF-directed targeting unresolved"]},{"year":2021,"claim":"Showed SMARCA4 loss collapses function of all three SWI/SNF subclasses (BAF/PBAF/GBAF), reducing accessibility at lineage TF motifs and driving dedifferentiation and metastasis.","evidence":"Conditional Smarca4 knockout lung cancer model with ATAC-seq, scRNA-seq, and SWI/SNF complex IP","pmids":["34561242"],"confidence":"High","gaps":["Subclass-specific contributions to phenotype not separated","Cell-type dependence mechanism unresolved"]},{"year":2020,"claim":"Linked SMARCA4 to genome stability and replication, showing SWI/SNF physically associates with RPA and that BRG1 loss causes CDC6-dependent origin firing and ATR-dependent replication stress.","evidence":"Reciprocal co-IP with quantitative MS, DNA fiber assays, and pharmacological ATR inhibition in lung cancer cells","pmids":["32690724"],"confidence":"Medium","gaps":["Direct vs transcriptional route to origin deregulation unresolved","Whether RPA interaction is functional at forks not demonstrated"]},{"year":2024,"claim":"Established that SMARCA4 loss derepresses long-terminal repeats and triggers STING/MAVS/IRF3-dependent innate immune signaling and immune infiltration, defining an immunogenic consequence of remodeler deficiency.","evidence":"SMARCA4 knockout ovarian cancer cells, RNA-seq, STING/MAVS/IRF3 knockdown epistasis, and immune flow cytometry in mouse tumors","pmids":["39630912"],"confidence":"Medium","gaps":["Whether repeat derepression is direct chromatin effect unresolved","Type-I-IFN-independent route mechanism not fully defined"]},{"year":2024,"claim":"Resolved a major targeting determinant by showing the esBAF AT-hook preferentially binds eRNA, recruiting SWI/SNF in cis to cell-type-specific enhancers and licensing MLL3/4, p300/CBP, and Mediator.","evidence":"AT-hook RNA binding assays, eRNA co-IP, and coactivator ChIP-seq across differentiation stages","pmids":["38593804"],"confidence":"Medium","gaps":["How eRNA stimulation reconciles with lncRNA inhibition of the same domain unresolved","Sequence specificity of eRNA engagement undefined"]},{"year":null,"claim":"How the competing inputs to BRG1 targeting and activity—TF recruitment, histone marks, AT-rich DNA, stimulatory eRNA versus inhibitory lncRNA, and phospho-regulation—are integrated to produce locus-specific accessibility decisions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model reconciling RNA stimulation vs inhibition at the AT-hook","Quantitative hierarchy of targeting determinants in vivo undefined","Structure of the full remodeler engaging a nucleosome plus RNA not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1,7,11,16]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,11,21]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[12,40]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7,16,39]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3,24,41]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[12,23]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,21,22]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[11,16,21]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,11,21,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,24,39,41]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,6,8,41]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25,26,38]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,24,17,37]}],"complexes":["SWI/SNF (BAF)","PBAF","GBAF","esBAF"],"partners":["STAT3","FBW7","OTUD6A","PRMT1","SOX10","RPA","HIF1A","STK11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51532","full_name":"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4","aliases":["BRG1-associated factor 190A","BAF190A","Mitotic growth and transcription activator","Protein BRG-1","Protein brahma homolog 1","SNF2-beta","Transcription activator BRG1"],"length_aa":1647,"mass_kda":184.6,"function":"ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:15075294, PubMed:29374058, PubMed:30339381, PubMed:32459350). Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating the calcium-dependent release of a repressor complex and the recruitment of an activator complex. In resting neurons, transcription of the c-FOS promoter is inhibited by SMARCA4-dependent recruitment of a phospho-RB1-HDAC repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CREBBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 complex also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves the release of HDAC1 and recruitment of CREBBP (By similarity). Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development, a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. SMARCA4/BAF190A may promote neural stem cell self-renewal/proliferation by enhancing Notch-dependent proliferative signals, while concurrently making the neural stem cell insensitive to SHH-dependent differentiating cues (By similarity). Acts as a corepressor of ZEB1 to regulate E-cadherin transcription and is required for induction of epithelial-mesenchymal transition (EMT) by ZEB1 (PubMed:20418909). Binds via DLX1 to enhancers located in the intergenic region between DLX5 and DLX6 and this binding is stabilized by the long non-coding RNA (lncRNA) Evf2 (By similarity). Binds to RNA in a promiscuous manner (By similarity). In brown adipose tissue, involved in the regulation of thermogenic genes expression (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P51532/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMARCA4","classification":"Not Classified","n_dependent_lines":422,"n_total_lines":1208,"dependency_fraction":0.34933774834437087},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000127616","cell_line_id":"CID001672","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"ARID1A","stoichiometry":10.0},{"gene":"PHF10","stoichiometry":10.0},{"gene":"BCL7A","stoichiometry":10.0},{"gene":"SMARCB1","stoichiometry":10.0},{"gene":"SMARCC1","stoichiometry":10.0},{"gene":"SMARCE1","stoichiometry":10.0},{"gene":"SMARCD1","stoichiometry":10.0},{"gene":"SMARCC2","stoichiometry":10.0},{"gene":"SS18","stoichiometry":10.0},{"gene":"SMARCD2","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001672","total_profiled":1310},"omim":[{"mim_id":"620843","title":"HEAT-SHOCK TRANSCRIPTION FACTOR 5; HSF5","url":"https://www.omim.org/entry/620843"},{"mim_id":"620792","title":"OTOSCLEROSIS 12; OTSC12","url":"https://www.omim.org/entry/620792"},{"mim_id":"620006","title":"RAD54-LIKE 2; RAD54L2","url":"https://www.omim.org/entry/620006"},{"mim_id":"618779","title":"COFFIN-SIRIS SYNDROME 11; CSS11","url":"https://www.omim.org/entry/618779"},{"mim_id":"618502","title":"BRD4-INTERACTING CHROMATIN REMODELING COMPLEX-ASSOCIATED PROTEIN-LIKE; BICRAL","url":"https://www.omim.org/entry/618502"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Supported"},{"location":"Nucleoli rim","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SMARCA4"},"hgnc":{"alias_symbol":["hSNF2b","BRG1","BAF190","SNF2","SWI2","SNF2-BETA","SNF2LB","FLJ39786"],"prev_symbol":["SNF2L4"]},"alphafold":{"accession":"P51532","domains":[{"cath_id":"-","chopping":"375-384_395-423","consensus_level":"medium","plddt":88.9085,"start":375,"end":423},{"cath_id":"3.40.50.10810","chopping":"734-981","consensus_level":"medium","plddt":83.97,"start":734,"end":981},{"cath_id":"3.40.50.300","chopping":"992-1257_1302-1330","consensus_level":"medium","plddt":82.5636,"start":992,"end":1330},{"cath_id":"1.20.920.10","chopping":"1457-1567","consensus_level":"medium","plddt":89.4411,"start":1457,"end":1567},{"cath_id":"1.20.5","chopping":"457-526","consensus_level":"high","plddt":83.8886,"start":457,"end":526}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51532","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51532-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51532-F1-predicted_aligned_error_v6.png","plddt_mean":64.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMARCA4","jax_strain_url":"https://www.jax.org/strain/search?query=SMARCA4"},"sequence":{"accession":"P51532","fasta_url":"https://rest.uniprot.org/uniprotkb/P51532.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51532/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51532"}},"corpus_meta":[{"pmid":"32709715","id":"PMC_32709715","title":"The 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Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/32376391","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51094,"output_tokens":11213,"usd":0.160739,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22359,"output_tokens":6038,"usd":0.131373,"stage2_stop_reason":"end_turn"},"total_usd":0.292112,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"BRG1 (SMARCA4) fractionates into two distinct complexes that differ in activity and subunit composition; both BRG1-containing complexes and the hBrm complex can remodel nucleosomal arrays, increase restriction enzyme accessibility, and hydrolyze ATP in a DNA-dependent manner. One BRG1 complex and the hBrm complex contain mSin3A components, and BRG1, hBrm, and BAF155 directly interact with mSin3A in vitro, linking hSWI/SNF to gene repression machinery.\",\n      \"method\": \"Epitope-tagged cell lines, biochemical fractionation, nucleosome remodeling assays, ATPase assays, restriction enzyme accessibility assays, in vitro pulldown\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of enzymatic activities (ATPase, remodeling), direct pulldown interaction, multiple orthogonal methods in one study\",\n      \"pmids\": [\"11238380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"LKB1 (STK11) physically associates with BRG1, requiring the N-terminus of LKB1 and the helicase domain of BRG1. LKB1 stimulates the ATPase activity of BRG1. Expression of a kinase-dead LKB1 mutant blocks BRG1-induced growth arrest (flat-cell formation) in SW13 cells, demonstrating LKB1 kinase activity is required for BRG1-dependent growth arrest.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping pulldown, ATPase activity assay, cell-based growth arrest assay with kinase-dead mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical ATPase assay plus domain-mapped co-IP plus functional epistasis in cell-based system, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11445556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"BRG1 reintroduction into BRG1-mutant breast tumor cells induces growth arrest accompanied by upregulation of CDK inhibitors p21 and p15; p21 protein is recruited to a complex with CDK2 to inhibit its activity. BRG1 associates with the p21 promoter in a p53-independent manner, suggesting direct transcriptional activation of p21.\",\n      \"method\": \"BRG1 re-expression in BRG1-null cells, microarray/RT-PCR, protein co-immunoprecipitation (p21-CDK2 complex), chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing BRG1 at p21 promoter plus co-IP of p21-CDK2 complex plus functional rescue, single lab\",\n      \"pmids\": [\"14673169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"STAT3 recruits BRG1 to the p21waf1 promoter upon cytokine stimulation; BRG1 loading results in increased chromatin accessibility at the proximal p21waf1 promoter and association of RNA Polymerase II, establishing BRG1 as a downstream effector of STAT3-mediated chromatin remodeling and transcription initiation.\",\n      \"method\": \"Co-immunoprecipitation, pulldown, chromatin immunoprecipitation (ChIP), Southern blot restriction enzyme accessibility assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus ChIP plus chromatin accessibility assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15286705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BRG1 disrupts a positioned nucleosome at the TG-repeat sequence in the CSF1 promoter and induces Z-DNA formation. Both BRG1 remodeling activity and Z-DNA formation are required cooperatively for effective chromatin remodeling of the CSF1 promoter; active transcription expands but is not required to initiate Z-DNA formation.\",\n      \"method\": \"Nucleosome positioning assays, chromatin remodeling assays, Z-DNA antibody immunoprecipitation, restriction enzyme accessibility, transcription inhibition experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple chromatin assays in single lab demonstrating cooperative mechanism, no independent replication\",\n      \"pmids\": [\"16537901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"BRG1 promotes COUP-TFII expression in venous endothelial cells during murine embryogenesis by binding conserved regulatory elements within the COUP-TFII promoter and remodeling chromatin to increase promoter accessibility, thereby governing venous specification. Conditional endothelial deletion of Brg1 results in downregulated COUP-TFII and aberrant arterial marker expression on veins.\",\n      \"method\": \"Conditional knockout mouse model, ChIP, chromatin accessibility assay, immunofluorescence\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at COUP-TFII promoter plus conditional KO with defined vascular phenotype, single lab\",\n      \"pmids\": [\"23406903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BRG1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at enhancers activated during mesoderm induction. BRG1 is also required to maintain Polycomb-mediated H3K27me3 repression at non-mesodermal developmental regulators, demonstrating a dual role in activating lineage-specific enhancers and maintaining repression of alternative lineage genes.\",\n      \"method\": \"ESC-based directed differentiation, Brg1 conditional knockout, ChIP-seq for H3K27ac and H3K27me3, gene expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with conditional KO in defined differentiation system, single lab\",\n      \"pmids\": [\"25813539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Evf2 lncRNA is present in a ribonucleoprotein complex with BRG1 (SMARCA4) and BAF170 (SMARCC2) in the developing mouse forebrain. Evf2 RNA directly inhibits BRG1 ATPase and chromatin remodeling activities in vitro. BRG1 interacts with DLX1 and Evf2 through distinct binding sites. RNA-mediated inhibition of BRG1 ATPase/remodeling is promiscuous in vitro. Coffin-Siris syndrome mutations localize to the BRG1 RNA-binding and DLX1-binding domains.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, in vitro ATPase assay, in vitro remodeling assay, nuclear colocalization imaging\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ATPase inhibition assay plus in vitro remodeling assay plus MS identification of complex plus co-IP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"26138476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Brg1 controls chromatin remodeling and transcriptional activation at the Pax7 promoter in muscle satellite cells, and is required for viability and proliferation of primary myoblasts. Loss of Brg1 causes apoptosis; reintroduction of catalytically active Brg1 or Pax7 rescues the apoptotic phenotype.\",\n      \"method\": \"Conditional Brg1 deletion in primary satellite cells, ChIP, apoptosis assays, rescue with active Brg1 vs. Pax7\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at Pax7 promoter plus conditional KO phenotype plus catalytically active rescue, single lab\",\n      \"pmids\": [\"26036967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BRG1 is required for glucocorticoid receptor (GR)-mediated transcription. BRG1 pre-occupies GR binding sites (GBSs) prior to hormone exposure and is required for recruitment of pioneer factors FOXA1 and GATA3 to GBSs. GR interaction with FOXA1 and GATA3 binding sites was restricted to sites pre-bound by BRG1.\",\n      \"method\": \"BRG1 knockdown in human breast cancer cells, ChIP-seq for BRG1/GR/FOXA1/GATA3, transcriptional activation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with BRG1 knockdown plus pioneer factor recruitment data, single lab\",\n      \"pmids\": [\"29792595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ku70 (XRCC6) associates with a BRG1 fragment encompassing the HSA and BRK domains. Ku70/86 and components of the TOP2β/PARP1 complex are required for NR-mediated SWI/SNF-dependent transcriptional activation from endogenous promoters. GR/BRG1-dependent TOP2β-mediated transient double-strand DNA breaks are required for efficient GR-stimulated transcription.\",\n      \"method\": \"BRG1 domain-fragment pulldown, ChIP, transcriptional activation assay, TOP2β inhibition experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped pulldown plus ChIP plus functional transcription assays, single lab\",\n      \"pmids\": [\"26055322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of chromatin remodeling. Heterozygous expression of dominant-negative SMARCA4 mutants alters the open chromatin landscape at thousands of sites, causing loss of DNA accessibility at active enhancers (H3K27ac loss, H3K4me1 retained) and inducing pro-oncogenic expression changes including increased MYC expression.\",\n      \"method\": \"ATPase mechanochemical analysis, ATAC-seq, ChIP-seq (H3K27ac, H3K4me1), Polycomb ChIP-seq, gene expression analysis in cells expressing dominant-negative mutants\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mechanochemical cycle disruption demonstrated plus ATAC-seq plus ChIP-seq across multiple chromatin marks, comprehensive mechanistic study\",\n      \"pmids\": [\"29323272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRG1 bromodomain (BRD) has moderate specificity for H3K14ac. Both BRG1 and hBRM BRDs have DNA-binding activity through a surface basic patch; the BRD and an adjacent AT-hook make multivalent contacts with DNA showing affinity for AT-rich elements. Histone-binding activity does not substantially contribute to nucleosome targeting in vitro, and neither BRD histone nor DNA binding contribute to global chromatin affinity of BRG1 in mouse ESCs.\",\n      \"method\": \"Biochemical binding assays, NMR, SELEX, mutagenesis of basic patch, in vitro nucleosome binding assays, mouse ESC chromatin binding\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural characterization plus mutagenesis plus in vitro binding assays plus cellular validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28706277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRG1 knockdown globally alters long-range genomic interactions and reduces TAD boundary strength, suggesting BRG1 affects nucleosome occupancy around CTCF sites at TAD boundaries and may regulate CTCF and topoisomerase complex recruitment.\",\n      \"method\": \"BRG1 knockdown, Hi-C/genome organization analysis, CTCF ChIP\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, knockdown with genome organization data, primarily review/commentary with limited new experimental data reported in abstract\",\n      \"pmids\": [\"28060558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SCFFBW7 ubiquitin ligase mediates BRG1 protein degradation. CK1δ phosphorylates BRG1 at Ser31/Ser35 residues to facilitate BRG1 binding to FBW7, leading to ubiquitination-mediated degradation. Stabilization of BRG1 in gastric cancer cells suppresses E-cadherin expression and promotes metastasis.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (Ser31/Ser35), ubiquitination assay, kinase assay, E-cadherin expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phosphorylation site mutagenesis plus ubiquitination assay plus co-IP plus functional downstream readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30177679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC3 inhibition by entinostat decreases SMARCA4 chromatin remodeling activity, which in turn derepresses miR-27a, leading to destabilization of PAX3:FOXO1 mRNA and chemotherapy sensitization in alveolar rhabdomyosarcoma cells.\",\n      \"method\": \"HDAC3 inhibition, SMARCA4 activity assays, miR-27a expression analysis, mRNA stability assays, in vivo mouse models\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pathway epistasis with multiple cellular and in vivo readouts, single lab\",\n      \"pmids\": [\"30459282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Xist lncRNA directly interacts with BRG1, and in vitro RNA binding inhibits nucleosome-remodeling and ATPase activities of BRG1. In cells, Xist expels BRG1 from the inactive X chromosome; Xist deletion allows selective return of BRG1 in cis, which correlates with cohesin binding and restoration of TADs and formation of de novo 'superloops'.\",\n      \"method\": \"In vitro ATPase assay, in vitro nucleosome remodeling assay, RNA-protein interaction assay, ChIP-seq, ATAC-seq, Hi-C, Xist deletion cell system\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ATPase inhibition plus in vitro remodeling assay plus genomic ChIP-seq plus structural domain analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30664740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTEN loss stabilizes BRG1 protein through inhibition of the AKT/GSK3β/FBXW7 axis. Increased BRG1 in PTEN-deficient prostate cancer cells drives chromatin remodeling into a protumorigenic transcriptome, creating a synthetic lethal dependency on BRG1.\",\n      \"method\": \"Genetically engineered mouse models, organoid assays, protein stability analysis, co-immunoprecipitation, ChIP, BRG1 inhibitor treatment\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GEM and organoid models plus ChIP plus protein stabilization mechanism, single lab\",\n      \"pmids\": [\"30496141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BRG1 interacts with KDM3A histone demethylase on the MUC1 promoter in a STAT1- and RelA-dependent manner, demethylating H3K9 to activate MUC1 transcription in breast cancer cells.\",\n      \"method\": \"ChIP, co-immunoprecipitation, siRNA knockdown of BRG1/KDM3A, histone modification analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — co-IP plus ChIP plus KD rescue, single lab single study\",\n      \"pmids\": [\"30824191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BRG1 interacts with RORγ and is recruited to the Elovl3 promoter; BRG1 also interacts with histone acetyltransferase p300 to activate Elovl3 transcription in response to androgen and TGF-β in prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, gene expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP plus ChIP, single lab, limited mechanistic validation\",\n      \"pmids\": [\"31154107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BRG1 (SMARCA4)-containing SWI/SNF complexes physically interact with RPA complexes, as shown by quantitative mass spectrometry and co-immunoprecipitation. BRG1 loss in lung cancer cells leads to increased origin firing mediated by CDC6 and activation of replication stress responses, creating dependency on ATR kinase.\",\n      \"method\": \"Co-immunoprecipitation, quantitative mass spectrometry, single-molecule replication fork dynamics (DNA fiber assay), pharmacological ATR inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with MS plus single-molecule replication assay plus functional ATR dependency, single lab\",\n      \"pmids\": [\"32690724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Acute depletion of BRG1 (via auxin-inducible degron in knock-in mice) leads to decreased nascent RNA production and RNA Polymerase II binding at many genes, correlated with loss of BRG1 occupancy, diminished chromatin accessibility at DHSs, decreased p300 binding, and narrower nucleosome spacing at TF motifs, enhancers, and TSSs. Acute BRG1 depletion also severely compromises TSA-induced histone acetylation.\",\n      \"method\": \"Auxin-inducible degron knock-in mouse, SLAM-seq (nascent RNA), ChIP-seq (RNAPII, BRG1, p300), ATAC-seq, nucleosome mapping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — acute depletion system (AID tag in mice) plus multiple orthogonal genome-wide methods (nascent RNA, ChIP-seq, ATAC-seq, nucleosome mapping) across multiple cell types\",\n      \"pmids\": [\"38811575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CK2 (casein kinase 2) interacts with Brg1 and phosphorylates it in a mitotic-specific manner (hyperphosphorylation during mitosis). CK2-mediated phosphorylation is associated with partitioning of Brg1 to soluble chromatin during mitosis, and this phosphorylation pattern is conserved across multiple cell types and organisms.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation/kinase assays, subcellular fractionation, cell-cycle synchronization, immunofluorescence in embryonic somites and primary myoblasts\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation plus kinase assay plus co-IP plus subcellular localization across multiple cell types, single lab\",\n      \"pmids\": [\"32019271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT1-mediated H4R3me2a histone modification directly recruits SMARCA4 to chromatin. SMARCA4 and PRMT1 cooperatively promote CRC progression by activating EGFR and TNS4 transcription. The SMARCA4 R1157W mutation enhances recruitment to H4R3me2a and increases SWI/SNF ATPase activity.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, ChIP, cell viability/migration assays, in vivo mouse CRC model, ATPase activity assay for R1157W mutant\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing H4R3me2a-dependent SMARCA4 recruitment plus functional knockdown assays plus in vivo model, single lab\",\n      \"pmids\": [\"33853662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Smarca4 loss impairs the function of all three classes of SWI/SNF complexes (BAF, PBAF, GBAF), resulting in decreased chromatin accessibility at lung lineage transcription factor motifs, ultimately driving dedifferentiated tumor states and accelerated metastasis in a cell-type-dependent manner.\",\n      \"method\": \"Conditional Smarca4 knockout mouse lung cancer model, ATAC-seq, scRNA-seq, chromatin accessibility analysis, SWI/SNF complex immunoprecipitation\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO plus ATAC-seq plus SWI/SNF complex function analysis across all three complex types, single lab comprehensive study\",\n      \"pmids\": [\"34561242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KDM2B interacts with Brg1 (the SWI/SNF ATPase subunit) to facilitate chromatin accessibility at the Il6 promoter specifically, and this interaction is required for IL-6 induction in macrophages/dendritic cells without altering histone demethylation at the locus.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, KDM2B-conditional knockout mice, ATAC/chromatin accessibility assay\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP plus conditional KO with specific cytokine phenotype, single lab\",\n      \"pmids\": [\"31197256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Brg1 is required for NKp46+ ILC3 differentiation by promoting T-bet expression. Brg1 binds to both the Tbx21 and Csf2 gene loci in ILC3s, promoting active histone modifications at Tbx21 (activating T-bet) and repressive modifications at Csf2 (suppressing GM-CSF), through a cell-intrinsic mechanism that restrains intestinal inflammation.\",\n      \"method\": \"ILC3-specific Brg1 conditional KO, mixed bone marrow chimera, flow cytometry, ChIP for histone modifications at Tbx21 and Csf2 loci\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO plus ChIP for histone marks plus cell-intrinsic chimera experiment, single lab\",\n      \"pmids\": [\"32612160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Neuronal activity induces BRG1 phosphorylation at a serine residue sensitive to CaMKII inhibition. Phosphorylation alters BRG1 interaction with the NuRD repressor complex and cohesin, modulating enhancer-promoter looping, RNA Pol II recruitment, and enhancer RNA expression. Non-phosphorylatable BRG1 knockin mice fail to efficiently induce activity-dependent genes and show anxiety-like phenotypes.\",\n      \"method\": \"CaMKII inhibition, BRG1 phosphorylation mapping, co-immunoprecipitation (NuRD, cohesin), ChIP-seq, enhancer RNA quantification, knockin mouse behavior phenotyping\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-site-specific knockin mice plus ChIP-seq plus co-IP demonstrating changed interactions, single lab\",\n      \"pmids\": [\"34260936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SMARCA4 loss renders lung cancer cells and primary SCCOHT cells highly sensitive to inhibition of KDM6A/UTX and KDM6B/JMJD3 histone demethylases. SMARCA4-mutant cells show impaired transactivation, aberrant H3K27me3 accumulation, and significantly reduced KDM6A/KDM6B levels compared to SMARCA4-intact cells.\",\n      \"method\": \"SMARCA4-mutant cell lines, KDM6 inhibitor (GSK-J4) treatment, in vivo orthotopic tumor models, H3K27me3 ChIP, gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link between SMARCA4 loss and H3K27me3 accumulation plus in vivo validation, single lab\",\n      \"pmids\": [\"34262032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OTUD6A deubiquitinase stabilizes BRG1 by erasing K27-linked polyubiquitination, thereby preventing its degradation in prostate cancer cells. OTUD6A catalytic activity (not dead-mutant) is required for this stabilization and for prostate cancer cell progression.\",\n      \"method\": \"Mass spectrometry substrate screening, co-immunoprecipitation, ubiquitination assay, catalytic dead mutant, in vivo PDX and GEM models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification plus ubiquitination assay plus catalytic mutant plus in vivo models, single lab\",\n      \"pmids\": [\"35233061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMARCA4/2 loss represses GLUT1 expression, reduces glucose uptake and glycolysis, and increases dependency on oxidative phosphorylation fueled by elevated glutamine import via SLC38A2. SMARCA4/2-deficient cells are sensitive to OXPHOS inhibitors and glutamine metabolism inhibitors; alanine supplementation competes with glutamine uptake via SLC38A2 and selectively kills SMARCA4/2-deficient cells.\",\n      \"method\": \"SMARCA4/2 double-knockout cells, metabolic flux assays, glucose uptake assays, SLC38A2 knockdown, in vitro and patient-derived xenograft treatment experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — metabolic mechanism defined with multiple functional assays and PDX validation, single lab\",\n      \"pmids\": [\"37210563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Hemogen recruits SWI/SNF complex ATPase BRG1 as a coactivator to regulate nucleosome accessibility and H3K27ac enrichment at erythroid gene promoters and enhancers. BRG1 is largely dependent on hemogen to regulate chromatin accessibility at erythroid gene promoters/enhancers in mouse fetal liver, as shown by hemogen-knockout animals.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq in WT and hemogen-KO mice, ATAC-seq, hemogen-knockout/knockin mouse models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq in KO animals plus co-IP plus ATAC-seq, single lab with in vivo KO validation\",\n      \"pmids\": [\"35297980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Brg1 loss leads to immediate increased tolerance to aneuploidy in chromosomally stable cells, and fitness recovery over time correlates with chromosome gain, demonstrating BRG1 normally suppresses aneuploidy tolerance.\",\n      \"method\": \"BRG1 deletion in chromosomally stable cell line, karyotype analysis, fitness/proliferation assays over time, proteomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct BRG1 deletion with karyotypic and fitness tracking, single lab\",\n      \"pmids\": [\"35365638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMARCA4 colocalizes with SOX10 at gene regulatory elements in diffuse midline glioma (DMG) cells; SMARCA4 chromatin binding is reduced upon depletion of SOX10 or H3.3K27M mutation. SMARCA4 controls expression of genes involved in cell growth and the extracellular matrix in DMG.\",\n      \"method\": \"ChIP-seq for SMARCA4 and SOX10, SMARCA4 KO/knockdown, H3.3K27M depletion, gene expression analysis, patient-derived xenograft models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq showing co-occupancy plus conditional depletion experiments, single lab\",\n      \"pmids\": [\"36305747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Brg1 interacts with lysine demethylase Kdm7aa in cardiac endothelial cells; this complex fine-tunes H3K4me3 at the promoter regions of Notch family genes, modulating Notch transcription during zebrafish heart regeneration. Dominant-negative Brg1 expression in endothelium causes abnormal Notch activation and inhibits myocardial regeneration.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq (H3K4me3), RNA-seq, endothelium-specific dominant-negative Brg1 overexpression in zebrafish\",\n      \"journal\": \"NPJ Regenerative medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus co-IP plus in vivo zebrafish genetic model, single lab\",\n      \"pmids\": [\"37029137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Brg1 directly binds to the CXCL14 promoter and activates its transcription in hepatocytes, driving neutrophil trafficking during alcoholic liver disease. Pharmaceutical inhibition of Brg1 with PFI-3 reduces CXCL14 expression and alleviates ALD pathogenesis.\",\n      \"method\": \"Hepatocyte-specific Brg1 manipulation, RNA-seq, ChIP at CXCL14 promoter, flow cytometry, PFI-3 small molecule inhibitor treatment, in vivo ALD mouse models\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at target promoter plus conditional KO with specific flow cytometric phenotype plus pharmacological validation, single lab\",\n      \"pmids\": [\"36722664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The SMARCA4 R1157W mutation facilitates recruitment to PRMT1-mediated H4R3me2a chromatin and enhances the ATPase activity of the SWI/SNF complex, reinforcing transcriptional activation of EGFR and TNS4 to promote CRC cell proliferation.\",\n      \"method\": \"SMARCA4 R1157W mutant expression, ATPase activity assay, ChIP, organoid proliferation assays, xenograft models, PRMT1/SMARCA4 inhibitor combination\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ATPase assay for mutant plus ChIP plus organoid/in vivo models, single lab\",\n      \"pmids\": [\"36922568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Brg1 controls stemness and metastasis of pancreatic ductal adenocarcinoma through regulation of the hypoxia pathway. Brg1 is required for HIF-1α to bind its target genes, augmenting the hypoxia transcriptional program that maintains cancer stem-like properties and enables liver metastasis.\",\n      \"method\": \"Dual recombinase conditional Brg1 deletion in established PDAC, splenic injection/peritoneal dissemination metastasis models, ChIP for HIF-1α binding, gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in established tumors plus ChIP for HIF-1α at target genes plus metastasis models, single lab\",\n      \"pmids\": [\"37198398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMARCA4 loss in ovarian cancer models results in up-regulation of long-terminal RNA repeats, increased expression of interferon-stimulated genes, and up-regulation of antigen presentation machinery, dependent on STING, MAVS, and IRF3 signaling but independent of type I interferon receptor. Mouse tumors with SMARCA4 loss show increased cytotoxic T cell, NK cell, and myeloid infiltration.\",\n      \"method\": \"SMARCA4 knockout in ovarian cancer cells, RNA-seq, STING/MAVS/IRF3 knockdown epistasis, immune cell flow cytometry in mouse tumor models, BRG1 inhibitor treatment of SMARCA4-proficient cells\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple pathway components plus in vivo immune phenotyping plus pharmacological validation, single lab\",\n      \"pmids\": [\"39630912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The BRG1 AT-hook of the esBAF complex preferentially binds RNA and associates with eRNA transcribed from intronic and intergenic regions. SWI/SNF is globally recruited in cis by eRNA to cell-type-specific enhancers; this facilitates recruitment of MLL3/4, p300/CBP, and Mediator to stage-specific enhancers and super-enhancers.\",\n      \"method\": \"RNA binding assays (AT-hook), eRNA co-immunoprecipitation, ChIP-seq for BRG1/MLL3/4/p300/Mediator at enhancers, cell lineage differentiation stages\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA binding assay plus ChIP-seq across differentiation stages plus coactivator co-occupancy, single lab\",\n      \"pmids\": [\"38593804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NMR spectroscopy and molecular modelling of the BRG1 AT-hook/bromodomain composite domain reveal the structural basis of DNA specificity. SELEX-seq identified preferred DNA sequences for this domain; cancer mutations in the DNA-binding pocket alter the mode of DNA association.\",\n      \"method\": \"NMR spectroscopy, SELEX-seq, molecular modelling, mutagenesis of cancer-associated residues\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural determination plus SELEX-seq plus mutagenesis of cancer mutations, single lab with multiple orthogonal Tier 1 methods\",\n      \"pmids\": [\"32376391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BRG1 binds to the Sox9 promoter in pancreatic acinar cells to regulate Sox9 expression and is critical for recruitment of upstream regulators PDX1 to the Sox9 promoter and enhancer. BRG1 loss blocks acinar-to-ductal metaplasia (ADM) and PanIN formation; Sox9 overexpression rescues the PanIN-attenuated phenotype of BRG1-deficient mice.\",\n      \"method\": \"Acinar-specific Brg1 conditional KO in Kras-mutant mice, ChIP at Sox9 promoter/enhancer, Sox9 overexpression rescue experiment, dual recombinase system for established PanIN deletion\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at Sox9 regulatory elements plus conditional KO plus genetic rescue (Sox9 overexpression) plus dual recombinase regression experiment, comprehensive single-lab study\",\n      \"pmids\": [\"30010625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRG1/BRM repress c-Myc expression in adult cardiomyocytes; loss of both BRG1 and BRM leads to upregulated c-MYC and progressive ventricular dysfunction with conduction defects. BRG1/BRM and c-MYC have opposite effects on cardiac conduction gene expression; BRG1/BRM occupancy is diminished at target genes in human heart failure cases.\",\n      \"method\": \"Tamoxifen-inducible cardiomyocyte-specific Brg1/Brm double KO, echocardiography, electrocardiography, inducible c-MYC overexpression, ChIP in human heart failure specimens\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional double KO with functional cardiac phenotype plus ChIP in human samples plus genetic epistasis with c-MYC, single lab\",\n      \"pmids\": [\"28232072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SMARCAL1 and BRG1 co-localize on the promoters of ATM and ATR; downregulation of both results in transcriptional repression of ATM/ATR and override of the G2/M checkpoint. On DNA damage, phospho-ATM binds to the promoters of SMARCAL1, BRG1, ATM, and ATR, creating a feedback regulatory loop.\",\n      \"method\": \"ChIP (SMARCAL1, BRG1 at ATM/ATR promoters), siRNA knockdown, cell cycle checkpoint assays, phospho-ATM ChIP\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP co-localization plus knockdown epistasis plus phospho-ATM feedback ChIP, single lab\",\n      \"pmids\": [\"30317028\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMARCA4/BRG1 is the catalytic ATPase subunit of mammalian SWI/SNF (BAF/PBAF/GBAF) chromatin remodeling complexes that uses ATP hydrolysis to reposition nucleosomes, increase chromatin accessibility at enhancers and promoters, and thereby activate or repress transcription; its chromatin binding, enzymatic activity, and protein stability are regulated by post-translational modifications including CK1δ/CK2-mediated phosphorylation (governing FBW7-mediated ubiquitin degradation), OTUD6A-mediated deubiquitination, CaMKII-induced neuronal activity-dependent phosphorylation, and recognition of the histone mark H4R3me2a; it is recruited to target loci through interactions with transcription factors (STAT3, GR, RORγ, SOX10, hemogen, NF-κB/RelA) and through its AT-hook/bromodomain binding to DNA and eRNA, and its activity can be inhibited by noncoding RNAs (Xist, Evf2); loss of SMARCA4 impairs all three SWI/SNF complex classes, reduces chromatin accessibility at lineage-specific enhancers, causes replication stress via CDC6-dependent origin firing and RPA complex uncoupling, and triggers STING/MAVS/IRF3-dependent innate immune signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMARCA4/BRG1 is the catalytic ATPase subunit of mammalian SWI/SNF (BAF/PBAF/GBAF) chromatin-remodeling complexes that hydrolyzes ATP to reposition nucleosomes and set chromatin accessibility at enhancers, promoters, and lineage-specific regulatory elements, with its loss impairing all three complex classes and collapsing accessibility at lineage transcription-factor motifs [#0, #24]. Acute degron-based depletion establishes BRG1 as a direct positive driver of transcription: it maintains chromatin accessibility at DNase-hypersensitive sites, nucleosome spacing at TF motifs, p300 recruitment, histone acetylation, and RNA Pol II loading at active loci [#21]. Genome-wide it co-localizes with H3K27ac at distal enhancers to support their activation while simultaneously maintaining Polycomb H3K27me3 repression of alternative-lineage genes, a dual activating/repressive function [#6, #11]. BRG1 is targeted to chromatin by a multivalent AT-hook/bromodomain composite domain that preferentially binds AT-rich DNA and RNA, including enhancer RNAs that recruit SWI/SNF in cis to cell-type-specific enhancers and license MLL3/4, p300/CBP, and Mediator loading [#12, #40, #39], and by recognition of PRMT1-deposited H4R3me2a [#23]. Locus specificity is conferred through interactions with transcription factors and cofactors including STAT3, glucocorticoid receptor (with FOXA1/GATA3 pioneer recruitment), SOX10, hemogen, HIF-1\\u03b1, and PDX1/SOX9 [#3, #9, #33, #31, #37, #41]. Its abundance is controlled by a phospho-degron axis in which CK1\\u03b4 phosphorylation of Ser31/Ser35 promotes FBW7-mediated ubiquitination and degradation, opposed by OTUD6A deubiquitination, while CaMKII-dependent activity-induced phosphorylation rewires its association with NuRD and cohesin to modulate enhancer-promoter looping [#14, #29, #27]. BRG1 ATPase and remodeling activities are directly inhibited in vitro by noncoding RNAs Xist and Evf2, with Xist expelling BRG1 from the inactive X to reorganize TADs [#7, #16]. Cancer missense mutations target the ATPase mechanochemical cycle to act dominant-negatively and reshape the accessible chromatin landscape toward pro-oncogenic programs such as MYC induction [#11]. SMARCA4 loss additionally provokes CDC6-dependent origin firing, uncoupling from RPA complexes and ATR-dependent replication stress, and derepresses long-terminal repeats to trigger STING/MAVS/IRF3-dependent innate immune signaling [#20, #38]. Coffin-Siris syndrome mutations map to its RNA- and DLX1-binding domains [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established BRG1 as a bona fide ATP-dependent nucleosome-remodeling enzyme that exists in distinct multi-subunit complexes and physically links to repressive machinery, defining its core biochemical activity.\",\n      \"evidence\": \"Biochemical fractionation, in vitro nucleosome remodeling and ATPase assays, and in vitro pulldown with mSin3A components in tagged cell lines\",\n      \"pmids\": [\"11238380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how distinct complexes select different genomic targets\", \"Repressive vs activating mode at endogenous loci not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed BRG1 ATPase activity is stimulated by an upstream kinase (LKB1) whose catalytic activity is required for BRG1-driven growth arrest, connecting remodeling to tumor-suppressor signaling.\",\n      \"evidence\": \"Domain-mapped co-IP, ATPase assay, and kinase-dead epistasis in SW13 growth-arrest assay\",\n      \"pmids\": [\"11445556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphorylation sites on BRG1 by LKB1 not mapped\", \"Mechanism of ATPase stimulation unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified BRG1 as a transcription-factor-recruited remodeler at the p21 promoter, showing STAT3 brings BRG1 to open chromatin and load RNA Pol II, framing it as a downstream effector of signaling pathways.\",\n      \"evidence\": \"BRG1 re-expression, co-IP, ChIP, and restriction-enzyme accessibility assays in tumor cells\",\n      \"pmids\": [\"14673169\", \"15286705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p53-independence of p21 activation not fully resolved\", \"Generalizability of TF-directed recruitment beyond p21 untested at the time\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated BRG1 remodeling can drive non-B DNA structural transitions (Z-DNA) cooperatively required for promoter remodeling, expanding its mechanism beyond simple nucleosome sliding.\",\n      \"evidence\": \"Nucleosome positioning, Z-DNA immunoprecipitation, and transcription-inhibition assays at the CSF1 promoter\",\n      \"pmids\": [\"16537901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-promoter observation\", \"Generality of Z-DNA coupling across BRG1 targets unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established BRG1 as a lineage-determining remodeler in vivo, activating tissue-specific enhancers and gene programs (COUP-TFII, Pax7, mesodermal enhancers) while also maintaining Polycomb repression of alternative lineages.\",\n      \"evidence\": \"Conditional Brg1 knockouts, ChIP/ChIP-seq for H3K27ac and H3K27me3, and rescue experiments in endothelium, satellite cells, and ESC differentiation\",\n      \"pmids\": [\"23406903\", \"26036967\", \"25813539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How BRG1 sustains repressive H3K27me3 mechanistically unresolved\", \"Direct vs indirect enhancer effects not fully separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed BRG1 cooperates with glucocorticoid receptor and DNA-break machinery, pre-marking GR binding sites and enabling pioneer-factor recruitment and TOP2\\u03b2-mediated transient double-strand breaks for transcription.\",\n      \"evidence\": \"BRG1 knockdown with ChIP-seq for GR/FOXA1/GATA3, domain pulldown of Ku70, and TOP2\\u03b2 inhibition transcription assays\",\n      \"pmids\": [\"29792595\", \"26055322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How BRG1 selects GR sites prior to hormone unknown\", \"Physiological role of break formation vs collateral damage unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined noncoding RNAs as direct inhibitors of BRG1 enzymatic activity, with Evf2 and later Xist binding and suppressing ATPase/remodeling, and Xist expelling BRG1 to reorganize X-chromosome TADs.\",\n      \"evidence\": \"MS, co-IP, in vitro ATPase and remodeling assays, and Hi-C/ChIP-seq in Xist-deletion cells\",\n      \"pmids\": [\"26138476\", \"30664740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro RNA inhibition is promiscuous; specificity in vivo unclear\", \"Whether eRNA stimulation and lncRNA inhibition share a binding mode unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped the structural basis of BRG1 chromatin targeting, showing the AT-hook/bromodomain composite preferentially binds AT-rich DNA over histone marks, with cancer mutations altering DNA association.\",\n      \"evidence\": \"NMR, SELEX-seq, mutagenesis of the basic patch, and in vitro/ESC binding assays\",\n      \"pmids\": [\"28706277\", \"32376391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of DNA binding to global targeting found minor; the dominant targeting determinant left open\", \"RNA-binding role of this domain not yet defined at this stage\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that cancer-associated ATPase mutations act dominant-negatively to disrupt the remodeling mechanochemical cycle and reshape the accessible chromatin landscape toward pro-oncogenic output including MYC.\",\n      \"evidence\": \"Mechanochemical analysis, ATAC-seq, and multi-mark ChIP-seq in cells expressing dominant-negative mutants\",\n      \"pmids\": [\"29323272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specific loci are selectively lost vs retained unresolved\", \"Link between accessibility loss and MYC induction not fully mechanistic\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a phospho-degron controlling BRG1 abundance, with CK1\\u03b4 phosphorylating Ser31/Ser35 to drive SCF-FBW7 ubiquitination and degradation, coupling protein turnover to oncogenic phenotypes.\",\n      \"evidence\": \"Site-directed mutagenesis, ubiquitination and kinase assays, and co-IP with downstream E-cadherin readout\",\n      \"pmids\": [\"30177679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals controlling CK1\\u03b4 phosphorylation unresolved\", \"Whether degradation is cell-cycle or context restricted unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended BRG1 abundance control upstream and reciprocally, with PTEN loss stabilizing BRG1 via the AKT/GSK3\\u03b2/FBXW7 axis and OTUD6A deubiquitinase removing K27-linked chains to prevent degradation, both creating BRG1 dependencies in cancer.\",\n      \"evidence\": \"GEM and organoid/PDX models, protein-stability and ubiquitination assays, and catalytic-dead OTUD6A controls\",\n      \"pmids\": [\"30496141\", \"35233061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between OTUD6A and FBW7 not co-defined\", \"Direct E3 vs DUB balance in normal cells unquantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified histone-mark- and signaling-directed recruitment of SMARCA4, including PRMT1-deposited H4R3me2a recruitment and CaMKII-dependent activity-induced phosphorylation that rewires NuRD/cohesin interactions and enhancer looping.\",\n      \"evidence\": \"ChIP-seq, co-IP, ATPase assays for the R1157W mutant, and phospho-site knockin mice with behavioral and eRNA readouts\",\n      \"pmids\": [\"33853662\", \"34260936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The CaMKII-targeted phosphosite not definitively mapped\", \"How H4R3me2a recruitment integrates with TF-directed targeting unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed SMARCA4 loss collapses function of all three SWI/SNF subclasses (BAF/PBAF/GBAF), reducing accessibility at lineage TF motifs and driving dedifferentiation and metastasis.\",\n      \"evidence\": \"Conditional Smarca4 knockout lung cancer model with ATAC-seq, scRNA-seq, and SWI/SNF complex IP\",\n      \"pmids\": [\"34561242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subclass-specific contributions to phenotype not separated\", \"Cell-type dependence mechanism unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked SMARCA4 to genome stability and replication, showing SWI/SNF physically associates with RPA and that BRG1 loss causes CDC6-dependent origin firing and ATR-dependent replication stress.\",\n      \"evidence\": \"Reciprocal co-IP with quantitative MS, DNA fiber assays, and pharmacological ATR inhibition in lung cancer cells\",\n      \"pmids\": [\"32690724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs transcriptional route to origin deregulation unresolved\", \"Whether RPA interaction is functional at forks not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that SMARCA4 loss derepresses long-terminal repeats and triggers STING/MAVS/IRF3-dependent innate immune signaling and immune infiltration, defining an immunogenic consequence of remodeler deficiency.\",\n      \"evidence\": \"SMARCA4 knockout ovarian cancer cells, RNA-seq, STING/MAVS/IRF3 knockdown epistasis, and immune flow cytometry in mouse tumors\",\n      \"pmids\": [\"39630912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether repeat derepression is direct chromatin effect unresolved\", \"Type-I-IFN-independent route mechanism not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved a major targeting determinant by showing the esBAF AT-hook preferentially binds eRNA, recruiting SWI/SNF in cis to cell-type-specific enhancers and licensing MLL3/4, p300/CBP, and Mediator.\",\n      \"evidence\": \"AT-hook RNA binding assays, eRNA co-IP, and coactivator ChIP-seq across differentiation stages\",\n      \"pmids\": [\"38593804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How eRNA stimulation reconciles with lncRNA inhibition of the same domain unresolved\", \"Sequence specificity of eRNA engagement undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing inputs to BRG1 targeting and activity\\u2014TF recruitment, histone marks, AT-rich DNA, stimulatory eRNA versus inhibitory lncRNA, and phospho-regulation\\u2014are integrated to produce locus-specific accessibility decisions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model reconciling RNA stimulation vs inhibition at the AT-hook\", \"Quantitative hierarchy of targeting determinants in vivo undefined\", \"Structure of the full remodeler engaging a nucleosome plus RNA not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1, 7, 11, 16]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 11, 21]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [12, 40]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7, 16, 39]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3, 24, 41]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [12, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 21, 22]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [11, 16, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 11, 21, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 24, 39, 41]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 6, 8, 41]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25, 26, 38]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 24, 17, 37]}\n    ],\n    \"complexes\": [\"SWI/SNF (BAF)\", \"PBAF\", \"GBAF\", \"esBAF\"],\n    \"partners\": [\"STAT3\", \"FBW7\", \"OTUD6A\", \"PRMT1\", \"SOX10\", \"RPA\", \"HIF1A\", \"STK11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":10,"faith_total":10,"faith_pct":100.0}}