{"gene":"SMARCA2","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":1993,"finding":"Human SMARCA2 (hBRM) was identified as a nuclear transcriptional co-activator that cooperates with the glucocorticoid receptor (GR) to activate transcription; cooperation required the DNA-binding domain of GR and two separated regions of hBRM including a helicase-homology domain.","method":"Transfection of hBRM into cells lacking endogenous hBRM, followed by transactivation assays with GR reporters; deletion analysis of hBRM domains","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transfection assay with domain-deletion analysis, single lab, two orthogonal approaches (reporter assay + domain mapping)","pmids":["8223438"],"is_preprint":false},{"year":1995,"finding":"Human SMARCA2 (hBRM) co-immunoprecipitates with hSNF5 (a human SNF5 homologue), and this interaction depends on the conserved SNF5-homology domain of hSNF5, indicating that hBRM and hSNF5 are subunits of a human SWI/SNF complex.","method":"Co-immunoprecipitation from cell extracts; interaction mapping with truncation mutants","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP demonstrated, interaction domain mapped, single lab","pmids":["7739891"],"is_preprint":false},{"year":1996,"finding":"During mitosis, SMARCA2 (hBRM) is phosphorylated and excluded from condensed chromosomes; mitotic phosphorylation correlates with decreased affinity for the nuclear structure in early M phase but does not disrupt the hBRM–hSNF5 association. Additionally, the level of hBRM protein is strongly reduced in mitosis.","method":"Cell fractionation, Western blot, immunofluorescence across cell cycle stages; co-immunoprecipitation of hBRM with hSNF5","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation plus IF plus co-IP, single lab, multiple orthogonal methods","pmids":["8670841"],"is_preprint":false},{"year":1996,"finding":"SMARCA2 (hBRM) interacts physically with the pRB family of proteins (pRB, p107, p130) via the LXCXE motif; hBRM requires an intact pRB-binding domain to induce growth arrest, and growth-arrest activity is antagonized by E1A.","method":"Yeast two-hybrid, transfection of wild-type and pRB-binding-deficient hBRM mutants into SW13 cells; colony-formation and flat-cell assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional mutagenesis assay, single lab","pmids":["8657132"],"is_preprint":false},{"year":1997,"finding":"SMARCA2 (hBRM) cooperates with RB to repress E2F1 transcriptional activity; RB bridges hBRM and E2F1 into a ternary complex in vivo; repression requires the RB-binding domain and the NTP-binding site of hBRM but not its bromodomain. The RB-binding domain of hBRM itself has transcriptional activation potential that RB can repress.","method":"Co-immunoprecipitation of E2F1–hBRM–RB complexes; transient transfection repression assays with hBRM deletion mutants; ATPase-dead and bromodomain mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, functional domain mutagenesis, and transcriptional assays in the same study; findings on RB–hBRM cooperation are foundational and mechanistically detailed","pmids":["9326598"],"is_preprint":false},{"year":1999,"finding":"A 49-amino-acid AT-hook-like domain in SMARCA2 (brm/SNF2α), rich in lysines and arginines and located downstream of the pRB interaction domain, is required for tethering of brm to chromatin and for cooperation with the glucocorticoid receptor on chromatin-integrated reporters; the LXCXE pRB-binding motif and bromodomain had only moderate effects on these activities.","method":"Transfection of deletion mutants into ras-transformed fibroblasts; transactivation assays on integrated vs. episomal reporters; domain-function correlation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple deletion mutants with two orthogonal functional readouts (transformation reversal + chromatin-integrated reporter), single lab","pmids":["10330133"],"is_preprint":false},{"year":2001,"finding":"Purified hBRM complex (containing hBRM as its central ATPase) can remodel nucleosomal arrays, increase restriction enzyme accessibility to nucleosomal DNA, and hydrolyze ATP in a DNA-dependent manner; the hBRM complex shows lower remodeling activity than BRG1-containing complexes and is markedly less active on mononucleosomal core particles. The hBRM complex also contains mSin3A and directly interacts with mSin3A in vitro.","method":"Epitope-tagged pull-down and fractionation of stable cell lines; in vitro ATPase assay; restriction enzyme accessibility assay on nucleosomal arrays; in vitro binding of hBRM to mSin3A","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution with enzymatic assays (ATPase, restriction enzyme accessibility, nucleosome remodeling) plus direct binding assay; multiple orthogonal methods in one study","pmids":["11238380"],"is_preprint":false},{"year":2001,"finding":"SYT-SSX1 oncofusion protein physically associates with SMARCA2 (hBRM/hSNF2α); the binding region maps to aa 1–181 of SYT-SSX1 and aa 156–205 of hBRM; overexpression of the hBRM binding region suppressed anchorage-independent growth of SYT-SSX1-expressing cells, indicating that hBRM interaction is functionally required for transformation.","method":"Co-immunoprecipitation from expressing cells; domain mapping; soft-agar anchorage-independent growth assay with hBRM fragment overexpression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping and functional rescue experiment, single lab","pmids":["11274403"],"is_preprint":false},{"year":2001,"finding":"SMARCA2 (hBRM) is cleaved during apoptosis by cathepsin G (not by caspases-3, -7, or -6); cleavage removes a 20-kDa C-terminal fragment containing the bromodomain and disrupts association of hBRM with the nuclear matrix; cathepsin G redistributes from granules/Golgi to a diffuse nuclear distribution during apoptosis.","method":"In vitro cleavage assay with recombinant/purified caspases and cathepsin G; peptide inhibitor of cathepsin G in apoptosis assay; nuclear matrix fractionation of cleaved vs. full-length hBRM","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro cleavage assay identifying cathepsin G, confirmed in vivo with specific peptide inhibitor, functional consequence (nuclear matrix dissociation) measured by fractionation; multiple orthogonal methods","pmids":["11259672"],"is_preprint":false},{"year":2002,"finding":"Prohibitin recruits SMARCA2 (Brm) to E2F-responsive promoters; this recruitment is required for prohibitin-mediated repression of E2F transcription and growth suppression; prohibitin-Brm-mediated repression requires RB but the initial association of prohibitin with Brm is RB-independent.","method":"Dominant-negative Brm rescue experiment; co-immunoprecipitation of prohibitin with Brm; chromatin immunoprecipitation at E2F-responsive promoters; growth suppression assays","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and dominant-negative functional assay in one study, single lab","pmids":["12065415"],"is_preprint":false},{"year":2002,"finding":"SMARCA2 (BRM) can functionally substitute for BRG1 to restore RB-mediated cell cycle arrest and induce CD44 expression when transfected into BRG1/BRM double-deficient tumor cell lines; however, CD44 expression specifically requires BRM (not BRG1) under physiological conditions in vivo, as demonstrated in BRM-null mice.","method":"Transient transfection of BRM into double-deficient tumor cells; analysis of BRM-null mouse tissues for CD44 expression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transfection assay corroborated by in vivo mouse knockout data, single lab","pmids":["11850839"],"is_preprint":false},{"year":2003,"finding":"SMARCA2 (BRM) but not BRG1 interacts with two ankyrin repeat proteins (components of Notch signal transduction) through protein-protein interactions unique to BRM, enabling BRM-containing SWI/SNF complexes to be recruited to Notch-responsive promoters during differentiation.","method":"Pulldown and co-immunoprecipitation identifying BRM-specific interactors; promoter occupancy analysis comparing BRG1 and BRM complexes","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP/pulldown demonstrating BRM-specific interaction, replicated with two orthogonal methods, single lab","pmids":["12620226"],"is_preprint":false},{"year":2004,"finding":"TopBP1 recruits SMARCA2 (Brm)/BRG1 to E2F1-responsive promoters and represses E2F1 (but not E2F2 or E2F3) transcriptional activity through a pRB-independent, Brg1/Brm-dependent mechanism, thereby suppressing E2F1-dependent apoptosis during normal cell growth and DNA damage.","method":"Co-immunoprecipitation of TopBP1 with Brm/BRG1; dominant-negative Brm rescue; ChIP at E2F1 promoters; apoptosis assays with Brm knockdown","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and functional dominant-negative experiments, single lab","pmids":["15075294"],"is_preprint":false},{"year":2004,"finding":"SMARCA2 (Brm)/BRG1 is required for estrogen antagonist-mediated growth suppression in breast cancer cells through E2F pathway repression; prohibitin recruits Brg1/Brm to promoter-bound E2F via a JNK1 pathway, and their recruitment is induced by estrogen antagonist treatment.","method":"Dominant-negative Brm/BRG1 rescue; ChIP at native E2F-responsive promoters; pharmacological JNK1 inhibition experiments","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus dominant-negative functional assays, single lab, multiple methods","pmids":["15141164"],"is_preprint":false},{"year":2007,"finding":"SMARCA2 (Brm)-containing SWI/SNF complexes, but not BRG1-containing complexes, are required for active repression of the osteocalcin promoter; BRM complexes bind the repressed osteocalcin promoter and are required for recruitment of the co-repressor HDAC1, whereas BRG1 complexes are required for activation.","method":"shRNA depletion of BRM and BRG1 separately; ChIP of BRM/BRG1 and HDAC1 at the osteocalcin promoter; osteoblast differentiation marker analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown combined with ChIP showing direct promoter occupancy and co-repressor recruitment, single lab","pmids":["19144648"],"is_preprint":false},{"year":2007,"finding":"Brm (SMARCA2) interacts with SHP nuclear receptor and facilitates SHP-mediated repression of CYP7A1 and auto-repression of SHP in bile acid feedback inhibition; ChIP showed Brm is recruited to both CYP7A1 and SHP promoters following FXR agonist treatment, resulting in inaccessible (repressed) chromatin. This is functionally distinct from BRG1, which interacts with FXR and promotes SHP transactivation.","method":"Co-immunoprecipitation of Brm with SHP; ChIP at CYP7A1 and SHP promoters; nucleosome remodeling assay; inducible knockdown/overexpression","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and in vitro chromatin accessibility assays in one study, single lab","pmids":["19805516"],"is_preprint":false},{"year":2007,"finding":"SMARCA2 (Brm) promotes retinal ganglion cell differentiation by facilitating expression and function of the transcription factor Brn3b and by inhibiting Notch signaling; Brm promotes cell cycle exit during this differentiation process.","method":"Perturbation of Brm expression and function in retinal progenitors; analysis of Brn3b expression and Notch signaling markers; cell cycle analysis","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function/overexpression with differentiation phenotype and Notch marker analysis, single lab, single main method","pmids":["17855369"],"is_preprint":false},{"year":2007,"finding":"SMARCA2 (Brm) is required for p21 induction by p53 specifically in BRG1-deficient cells; in cells expressing BRG1, BRG1 is the preferentially recruited ATPase for p53-dependent p21 activation. Impaired p21 induction upon BRG1 knockdown is partly due to decreased p53 binding to the p21 promoter.","method":"Inducible knockdown of Brm and BRG1 separately; p21/MDM2 mRNA quantification; ChIP of p53 at the p21 promoter","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible knockdown with ChIP evidence for promoter occupancy, single lab, two orthogonal methods","pmids":["17938176"],"is_preprint":false},{"year":2007,"finding":"Epigenetic silencing is the primary mechanism of BRM/SMARCA2 loss in cancer: HDAC inhibitors restore BRM expression in BRM/BRG1-deficient cancer cell lines despite the absence of inactivating mutations; HDAC inhibitors also block BRM function (via C-terminal acetylation) when present, but BRM activity is detectable after their removal.","method":"Sequencing of BRM in BRM-deficient lines (no mutations found); nuclear run-on and RT-PCR; HDAC inhibitor treatment; BRM activity assays post-inhibitor withdrawal","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutation sequencing plus functional epigenetic rescue experiments, single lab","pmids":["17546055"],"is_preprint":false},{"year":2008,"finding":"SMARCA2 (Brm) transactivates the TERT gene and modulates splicing patterns of TERT transcripts; Brm co-localizes with p54(nrb), PSF, and phospho-Ser2 RNA Pol II at TERT exon 7 alternative splicing acceptor sites; Brm knockdown in BRG1-deficient cells reduces TERT expression and increases exon-7/8-excluded (inactive) TERT mRNA, leading to growth arrest.","method":"shRNA knockdown of Brm; RT-PCR for TERT splice variants; ChIP showing co-localization of Brm with splicing factors at TERT; co-immunoprecipitation of p54(nrb) with Brm/BRG1","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — shRNA knockdown, ChIP, co-IP, and splice-form analysis, single lab, multiple orthogonal methods","pmids":["18042045"],"is_preprint":false},{"year":2009,"finding":"SMARCA2 (Brm) knockdown in Smarca2-knockout mice impairs social interaction and prepulse inhibition (schizophrenia-relevant behaviors); a missense risk SNP (rs2296212) reduces nuclear localization efficiency of BRM; intronic risk alleles (rs3763627, rs3793490) are associated with reduced SMARCA2 expression in prefrontal cortex.","method":"Smarca2 knockout mouse phenotyping (social interaction, PPI); cell-based nuclear localization assay for missense variant; postmortem brain expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with defined behavioral phenotype plus cell-based localization experiment, single lab","pmids":["19363039"],"is_preprint":false},{"year":2009,"finding":"SMARCA2 (Cdx2) and Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells; GST pull-down demonstrated a direct interaction between Cdx2 and several SWI/SNF subunits; ChIP showed co-recruitment of Cdx2 and Brm to the villin promoter HCR-Cdx element.","method":"GST pull-down; ChIP; reporter assays; Cdx2 knockdown","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction demonstrated by pulldown, confirmed by ChIP at native promoter, single lab","pmids":["19371634"],"is_preprint":false},{"year":2010,"finding":"REQ/DPF2 (requiem) acts as an adaptor that bridges SMARCA2 (Brm)-containing SWI/SNF complex and the NF-κB subunit p52; REQ binds Brm and p52 simultaneously; Brm and REQ are recruited to the BLC/CXCL13 promoter upon lymphotoxin stimulation and are both required for noncanonical NF-κB-dependent BLC transcription.","method":"In vitro binding assays (co-IP); ChIP at BLC promoter; REQ knockdown experiments; reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus ChIP plus knockdown, single lab","pmids":["20460684"],"is_preprint":false},{"year":2011,"finding":"SMARCA2 (Brm) loss in cancer cells results from post-transcriptional suppression (cells efficiently transcribe BRM but mRNA and pre-mRNA are undetectable), and can be reversed by HDAC inhibitor treatment, demonstrating that the BRM gene is intact and functional in these tumor lines.","method":"Nuclear run-on transcription assay; RT-PCR for BRM mRNA and hnRNA; HDAC inhibitor rescue experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear run-on plus RT-PCR orthogonal methods establishing post-transcriptional regulation, single lab","pmids":["16007216"],"is_preprint":false},{"year":2011,"finding":"BRM expression is regulated at the transcriptional level by the BRM promoter; two novel BRM promoter insertion polymorphisms (BRM-741 and BRM-1321) create MEF2-binding sites that recruit HDAC-containing complexes, leading to BRM silencing; MEF2D and HDAC9 bind these polymorphic sites (as shown by ChIP) and HDAC9 is overexpressed in BRM-negative cancer cell lines.","method":"BRM promoter sequencing; promoter swap ChIP experiments; HDAC9/MEF2D knockdown; ChIP at polymorphic sites","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct promoter binding of regulatory factors, knockdown experiments, and promoter swap approach, single lab","pmids":["21478907"],"is_preprint":false},{"year":2011,"finding":"SMARCA2 (hBRM) interacts with STAT1 in vitro; native (unphosphorylated) STAT1 selectively recruits hBRM to IFNγ-activated sequences (GAS) under basal conditions, where hBRM exists in a mSin3/HDAC co-repressor complex maintaining repressed chromatin; upon stress, hBRM is acetylated by p300 and dissociates from the repressor complex, while phospho-STAT1 recruits BRG1 instead — an hBRM-to-BRG1 switch that activates gene expression.","method":"Co-IP of hBRM with STAT1; ChIP at GAS elements; chromatin accessibility assays; p300 acetylation experiments","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, and accessibility assays in one study, single lab","pmids":["21079652"],"is_preprint":false},{"year":2012,"finding":"Drosophila BRM (ortholog of SMARCA2) physically associates with CBP acetyltransferase and the H3K27 demethylase UTX in vivo; BRM binds directly to conserved zinc fingers of CBP via its bromodomain-containing C-terminus; the BRM bromodomain enhances CBP PHD binding to histone H3 and stimulates in vitro acetylation of H3K27; brm mutations reduce H3K27ac and increase H3K27me3 levels.","method":"Co-immunoprecipitation and direct binding assays; in vitro acetylation assay with recombinant CBP; brm mutant analysis of histone marks; genome-wide ChIP co-localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding mapped to specific domains, in vitro enzymatic assay (H3K27 acetylation), in vivo co-IP, and genetic phenotype; multiple orthogonal methods in one study","pmids":["22493065"],"is_preprint":false},{"year":2013,"finding":"SMARCA2 (BRM) and BRG1 are required as coactivators for a subset of hypoxia-inducible factor (HIF) target genes; HIF1/HIF2 recruit BRG1 complexes to target gene promoters, which promotes nucleosome remodeling in a BRG1 ATPase-dependent manner; BRM depletion in BRG1/BRM-deficient cells reduces hypoxic induction of HIF targets.","method":"BRG1/BRM knockdown; re-expression of BRG1/BRM in deficient cells; ChIP at HIF target promoters; nucleosome remodeling assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus re-expression plus ChIP and nucleosome remodeling assay, single lab","pmids":["23897427"],"is_preprint":false},{"year":2013,"finding":"HDAC3 and HDAC9 regulate SMARCA2 (BRM) expression, whereas HDAC2 controls BRM acetylation; KAT6A, KAT6B, and KAT7 histone acetyltransferases induce BRM expression, and KAT2B and KAT8 induce its acetylation; the MAP kinase pathway regulates both BRM acetylation and BRM silencing.","method":"Selective siRNA knockdown of individual HDACs and overexpression of 21 HATs; MAPK pathway inhibitor treatment; BRM expression and acetylation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — systematic siRNA screen plus overexpression experiments, single lab, replicated across multiple targets","pmids":["23524580"],"is_preprint":false},{"year":2014,"finding":"SMARCA2 (BRM) is the catalytic ATPase of a residual SWI/SNF complex that is essential for proliferation of SMARCA4 (BRG1)-mutant cancer cells; loss of SMARCA4 leads to greater incorporation of SMARCA2 into SWI/SNF complexes; SMARCA2 depletion in SMARCA4-mutant cells causes cell cycle arrest, senescence, and increased global H3K9me3.","method":"shRNA-based loss-of-function screens across 165 cancer cell lines; co-immunoprecipitation demonstrating residual SMARCA2-containing complex; in vivo xenograft experiments; H3K9me3 immunofluorescence","journal":"Molecular and cellular biology / Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — large-scale functional screen corroborated by co-IP, in vivo xenograft model, and histone mark analysis; independently replicated across two concurrent papers (PMIDs 24421395 and 24520176)","pmids":["24421395","24520176"],"is_preprint":false},{"year":2014,"finding":"Drosophila BRM complex (SWI/SNF) associates physically with Earmuff transcription factor and HDAC3 to suppress dedifferentiation of intermediate neural progenitors (INPs) back into neuroblasts; multiple BRM complex components co-immunoprecipitate with Erm; brm and hdac3 genetically interact with erm to prevent type II neuroblast overgrowth.","method":"Co-immunoprecipitation of BRM complex subunits with Erm; genetic epistasis (double mutant analysis); brm and hdac3 knockdown phenotyping","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genetic epistasis demonstrating functional cooperation, single lab","pmids":["24618901"],"is_preprint":false},{"year":2017,"finding":"The bromodomain (BRD) of SMARCA2 (hBRM) has moderate specificity for H3K14ac; both BRG1 and hBRM BRDs also possess DNA-binding activity via a basic patch surface, and the BRD together with an adjacent AT-hook makes multivalent contacts with AT-rich DNA elements with robust affinity; however, histone-binding activity does not substantially contribute to nucleosome targeting in vitro, and global chromatin affinity of BRG1 in mouse ESCs does not require BRD histone or DNA binding.","method":"Binding assays (ITC/SPR) with modified histone peptides and DNA; mutagenesis of basic patch; nucleosome-binding assays; ChIP-seq in BRD-mutant mouse ESCs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding assays with mutagenesis and structural mapping plus in vivo ChIP-seq validation; multiple orthogonal methods in one study","pmids":["28706277"],"is_preprint":false},{"year":2017,"finding":"SMARCA2 expression is suppressed by PRC2 (EZH2-mediated H3K27me3) in SMARCA4-mutant cancer cells sensitive to EZH2 inhibition; induction of SMARCA2 expression by EZH2 inhibitors is required for apoptosis (but not growth arrest) through derepression of the lysosomal protease cathepsin B; re-expression of SMARCA2 can compensate for SMARCA4 loss and antagonize PRC2 targets.","method":"EZH2 inhibitor treatment; SMARCA2 re-expression experiments; RNAi depletion; gene expression analysis; in vivo xenograft models","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection using re-expression and RNAi with in vivo confirmation, single lab","pmids":["29087303"],"is_preprint":false},{"year":2017,"finding":"BRM/SMARCA2 contains a DNA-dependent ATPase activity that is allosterically inhibitable by small molecules; allosteric BRM/BRG1 dual inhibitors downregulate BRM-dependent gene expression and show antiproliferative activity in BRG1-mutant xenograft models.","method":"ATPase inhibition assay; gene expression analysis after inhibitor treatment; oral xenograft tumor model","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct enzymatic ATPase assay confirmed allosteric inhibition; in vivo functional validation, single lab","pmids":["30339381"],"is_preprint":false},{"year":2017,"finding":"BRM/SMARCA2 activates JAK2/STAT3 signaling in pancreatic cancer cells; BRM knockdown reduces STAT3 phosphorylation and transcription of STAT3 target genes, reducing proliferation and increasing gemcitabine sensitivity in vitro and in vivo.","method":"shRNA knockdown; Western blot for pSTAT3; RT-PCR for STAT3 targets; xenograft tumor model","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — knockdown with pathway marker readout, no direct binding or ChIP, single lab","pmids":["28602977"],"is_preprint":false},{"year":2019,"finding":"SMARCA2 (BRM) directly binds to the promoter regions of Claudin genes via interaction with transcription factor Sp1, activates Claudin transcription by modulating histone modifications, and its downregulation drives TGF-β-induced breast cancer cell migration/invasion; TGF-β represses BRM transcription through targeting C/EBPβ.","method":"ChIP of BRM at Claudin promoters; co-IP of BRM with Sp1; BRM overexpression/knockdown; migration/invasion assays","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct promoter binding plus co-IP with Sp1 plus functional migration assay, single lab","pmids":["30946989"],"is_preprint":false},{"year":2021,"finding":"SMARCA2 interacts with NSD2 in a noncanonical manner independent of the full SWI/SNF complex in t(4;14) multiple myeloma; the NSD2–SMARCA2 complex occupies the PTP4A3 promoter, leading to focal H3K36me2 enrichment and transcriptional activation of PTP4A3; PFI-3 (bromodomain inhibitor of SMARCA2) displaces NSD2 from the PTP4A3 promoter and inhibits myeloma cell viability.","method":"SILAC-based mass spectrometry identifying NSD2–SMARCA2 interaction; co-IP; ChIP of NSD2 and SMARCA2 at PTP4A3 promoter; H3K36me2 ChIP; PFI-3 treatment with ChIP; xenograft in vivo","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — mass spectrometry identification, reciprocal co-IP, ChIP mapping interaction to PTP4A3 promoter with histone mark, and functional rescue with bromodomain inhibitor; multiple orthogonal methods, in vivo validation","pmids":["33602783"],"is_preprint":false},{"year":2021,"finding":"The bromodomains of BRM and BRG1 promote stable chromatin binding at target promoters required for skeletal muscle differentiation; pharmacological inhibition with PFI-3 reduced BRM/BRG1 binding to promoters of myogenic genes, impaired cell cycle exit and muscle-specific gene expression both in vitro and in vivo.","method":"PFI-3 bromodomain inhibitor; ChIP of BRM/BRG1 after PFI-3 treatment; BRM/BRG1 shRNA depletion; differentiation marker analysis; in vivo muscle regeneration model","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical inhibition with ChIP validation and in vivo confirmation, single lab","pmids":["34289068"],"is_preprint":false},{"year":2022,"finding":"A VHL-recruiting PROTAC (ACBI2) achieves selective degradation of SMARCA2 over SMARCA4 in vivo, demonstrating that structural differences between the two paralogs can be exploited for selective targeted degradation; SMARCA2 degradation shows antitumor efficacy in SMARCA4-deficient cancer models.","method":"Structure-guided PROTAC design; cellular degradation assays; ex vivo human whole blood assay; in vivo xenograft model with selective SMARCA2 degradation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-guided design with in vitro degradation assays, ex vivo blood assay, and in vivo xenograft validation; selective over SMARCA4 confirmed","pmids":["36216795"],"is_preprint":false},{"year":2024,"finding":"SETMAR methylates dimethylated H3K36 in the SMARCA2 promoter region to promote SMARCA2 transcription; SMARCA2 in turn binds enhancers of thyroid differentiation transcription factors PAX8 and FOXE1 to promote their expression by enhancing chromatin accessibility; METTL3-mediated m6A methylation of SETMAR mRNA regulates this axis.","method":"ChIP of SMARCA2 at PAX8/FOXE1 enhancers; ATAC-seq for chromatin accessibility; SETMAR knockdown/overexpression; H3K36 methylation assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and ATAC-seq with functional knockdown, single lab","pmids":["38900084"],"is_preprint":false}],"current_model":"SMARCA2 (BRM/hBRM) is the DNA-dependent ATPase catalytic subunit of one class of human SWI/SNF (BAF) chromatin-remodeling complexes, where it uses ATP hydrolysis to remodel nucleosomal arrays; it is functionally distinct from its paralog SMARCA4 (BRG1), forming mutually exclusive complexes that differentially recruit transcription factors (e.g., glucocorticoid receptor, SHP, STAT1, Notch components, Cdx2, Sp1) and co-repressors (HDAC1, mSin3A) to specific promoters and enhancers to either activate or repress target genes; it is physically regulated by pRB (which bridges hBRM to E2F1 to repress proliferative genes), cleaved during apoptosis by cathepsin G (releasing it from the nuclear matrix), phosphorylated and excluded from chromosomes during mitosis, and epigenetically silenced in many cancers through HDAC3/HDAC9-dependent promoter mechanisms; in SMARCA4-mutant cancers, residual SMARCA2-containing SWI/SNF complexes become essential for tumor cell survival, establishing a synthetic lethal dependency that is therapeutically exploitable by selective SMARCA2 degraders (PROTACs) or allosteric ATPase inhibitors."},"narrative":{"mechanistic_narrative":"SMARCA2 (BRM/hBRM) is the DNA-dependent ATPase catalytic subunit of a class of human SWI/SNF chromatin-remodeling complexes that uses ATP hydrolysis to remodel nucleosomal arrays and govern transcription during differentiation, cell-cycle control, and tumor suppression [PMID:11238380, PMID:7739891]. Purified hBRM-containing complexes increase restriction-enzyme accessibility on nucleosomal arrays and hydrolyze ATP in a DNA-dependent manner, though they are markedly less active than BRG1/SMARCA4-containing complexes, and they incorporate the co-repressor mSin3A [PMID:11238380]. Chromatin targeting is multivalent: an AT-hook-like domain tethers BRM to chromatin and is required for cooperation with the glucocorticoid receptor, while the bromodomain shows modest H3K14ac preference and, with the adjacent AT-hook, binds AT-rich DNA, contributing to stable promoter occupancy [PMID:10330133, PMID:28706277]. BRM acts as a cofactor that is recruited by, and confers specificity through, partners distinct from those used by BRG1 — including the pRB family, which bridges BRM to E2F1 to repress proliferative genes and impose growth arrest, and a series of sequence-specific factors (SHP, STAT1, Notch-associated ankyrin proteins, Cdx2, Sp1, NF-κB p52 via the REQ/DPF2 adaptor) that direct it to specific promoters and enhancers for either activation or repression, frequently via recruitment of co-repressors such as HDAC1 [PMID:9326598, PMID:8657132, PMID:19805516, PMID:21079652, PMID:19371634, PMID:20460684, PMID:19144648, PMID:30946989]. BRM activity and abundance are regulated post-translationally and epigenetically — it is cleaved during apoptosis by cathepsin G to release it from the nuclear matrix, phosphorylated and excluded from chromosomes during mitosis, and silenced in many cancers through HDAC/MEF2-dependent promoter polymorphisms and PRC2-mediated H3K27me3 despite an intact, mutation-free gene [PMID:11259672, PMID:8670841, PMID:21478907, PMID:29087303, PMID:16007216]. In SMARCA4-mutant cancers, residual SMARCA2-containing SWI/SNF complexes become essential for proliferation, defining a synthetic-lethal dependency exploitable by selective SMARCA2 PROTAC degraders and allosteric ATPase inhibitors [PMID:24421395, PMID:24520176, PMID:36216795, PMID:30339381]. Genetic variants reducing SMARCA2 nuclear localization and expression are associated with schizophrenia-relevant behavioral phenotypes [PMID:19363039].","teleology":[{"year":1993,"claim":"Established SMARCA2 as a nuclear transcriptional co-activator, answering whether the human BRM protein had a transcriptional function and revealing it requires both a helicase-homology domain and partner DNA-binding factors.","evidence":"Transfection of hBRM into hBRM-deficient cells with GR reporter transactivation and domain-deletion mapping","pmids":["8223438"],"confidence":"Medium","gaps":["Did not establish enzymatic mechanism or complex membership","Cooperation with GR shown on reporters, not native loci"]},{"year":1995,"claim":"Placed hBRM within a multi-subunit human SWI/SNF complex by demonstrating physical association with hSNF5, answering whether the human protein assembles into a complex like its yeast counterpart.","evidence":"Co-immunoprecipitation with truncation-mutant interaction mapping","pmids":["7739891"],"confidence":"Medium","gaps":["Full complex composition not defined","No demonstration of remodeling activity"]},{"year":1996,"claim":"Defined cell-cycle regulation of BRM, showing it is phosphorylated, excluded from condensed chromosomes, and reduced in abundance during mitosis without disrupting the hBRM–hSNF5 interaction.","evidence":"Cell fractionation, immunofluorescence across cell-cycle stages, and co-IP","pmids":["8670841"],"confidence":"Medium","gaps":["Responsible mitotic kinase not identified","Functional consequence of chromosomal exclusion not established"]},{"year":1996,"claim":"Connected BRM to growth control by showing LXCXE-mediated interaction with the pRB family is required for BRM-induced growth arrest, antagonized by E1A.","evidence":"Yeast two-hybrid plus colony-formation/flat-cell assays with pRB-binding-deficient mutants","pmids":["8657132"],"confidence":"Medium","gaps":["Target genes of the arrest program not defined","Mechanism of pRB-BRM cooperation at promoters not resolved"]},{"year":1997,"claim":"Resolved the mechanism of BRM-mediated repression by demonstrating RB bridges BRM and E2F1 into a ternary complex requiring the RB-binding domain and ATPase site but not the bromodomain.","evidence":"Reciprocal co-IP of E2F1–hBRM–RB, transcriptional repression assays, and ATPase-dead/bromodomain mutants","pmids":["9326598"],"confidence":"High","gaps":["Which E2F target genes are physiologically controlled not fully mapped","In vitro repression vs. native promoter occupancy distinction limited"]},{"year":1999,"claim":"Identified the AT-hook-like domain as the chromatin-tethering module required for cooperation with GR on integrated (chromatinized) reporters, distinguishing chromatin targeting from pRB-binding and bromodomain functions.","evidence":"Deletion-mutant transfection with integrated vs. episomal reporter transactivation in ras-transformed fibroblasts","pmids":["10330133"],"confidence":"Medium","gaps":["Direct DNA/chromatin binding of the AT-hook not biochemically resolved here","Genome-wide targeting role untested"]},{"year":2001,"claim":"Provided direct biochemical proof that the hBRM complex is a bona fide ATP-dependent remodeler, establishing DNA-dependent ATPase and nucleosome-remodeling activity and lower activity than BRG1 complexes.","evidence":"Purified complex with in vitro ATPase, restriction-enzyme accessibility, nucleosome-array remodeling assays, and mSin3A binding","pmids":["11238380"],"confidence":"High","gaps":["Structural basis of lower activity vs. BRG1 not determined","Physiological significance of mSin3A association not tested in cells"]},{"year":2001,"claim":"Linked BRM to oncogenesis and to apoptotic regulation through two studies: SYT-SSX1 fusion requires BRM binding for transformation, and BRM is cleaved by cathepsin G during apoptosis to release it from the nuclear matrix.","evidence":"Co-IP/domain mapping with soft-agar assays; in vitro cathepsin G cleavage with inhibitor and nuclear-matrix fractionation","pmids":["11274403","11259672"],"confidence":"High","gaps":["Functional consequence of nuclear-matrix release for transcription not measured","Whether cathepsin G cleavage is a general apoptotic event unresolved"]},{"year":2002,"claim":"Demonstrated factor-directed recruitment of BRM to E2F promoters via prohibitin and showed BRM can functionally substitute for BRG1 in RB-mediated arrest while having a unique requirement for CD44 expression.","evidence":"Co-IP, ChIP at E2F promoters, dominant-negative rescue; transfection into double-deficient cells and BRM-null mouse tissue analysis","pmids":["12065415","11850839"],"confidence":"Medium","gaps":["Why some targets require BRM specifically not mechanistically explained","Prohibitin–BRM interaction interface not mapped"]},{"year":2003,"claim":"Established the paralog-specificity principle by showing BRM, but not BRG1, uses unique protein interactions (Notch-associated ankyrin repeat proteins) to occupy distinct promoters during differentiation.","evidence":"Pulldown/co-IP of BRM-specific interactors and promoter occupancy comparison","pmids":["12620226"],"confidence":"Medium","gaps":["Structural basis of BRM-specific interaction not defined","Breadth of BRM-exclusive interactome unknown"]},{"year":2004,"claim":"Extended BRM's E2F1-repressive role to a pRB-independent, TopBP1-recruited mechanism that suppresses E2F1-dependent apoptosis, broadening the recruitment routes that target BRM/BRG1 to E2F promoters.","evidence":"Co-IP of TopBP1, ChIP at E2F1 promoters, dominant-negative rescue, apoptosis assays; ChIP plus JNK1 inhibition in breast cancer cells","pmids":["15075294","15141164"],"confidence":"Medium","gaps":["Selectivity for E2F1 over E2F2/3 mechanistically unexplained","Direct vs. indirect TopBP1–BRM contact not mapped"]},{"year":2007,"claim":"Consolidated BRM as a context-specific activator or repressor through distinct partners (SHP, p53/p21, osteocalcin/HDAC1, Brn3b) and identified epigenetic silencing as the primary route of BRM loss in cancer.","evidence":"Separate shRNA/inducible knockdown, ChIP, and chromatin accessibility studies; BRM sequencing showing no mutations and HDAC-inhibitor rescue","pmids":["19805516","17938176","19144648","17855369","17546055"],"confidence":"Medium","gaps":["Rules governing activation vs. repression at a given locus not unified","RGC differentiation role rests on single low-confidence study"]},{"year":2008,"claim":"Linked BRM to co-transcriptional RNA processing by showing it transactivates TERT and modulates TERT splicing in association with p54(nrb)/PSF and elongating Pol II.","evidence":"shRNA knockdown, splice-variant RT-PCR, ChIP co-localization, and co-IP of splicing factors","pmids":["18042045"],"confidence":"Medium","gaps":["Direct role of remodeling vs. splicing-factor scaffolding not separated","Generality across other genes untested"]},{"year":2009,"claim":"Connected SMARCA2 to neurodevelopmental phenotypes and identified regulatory and missense variants affecting expression and nuclear localization relevant to schizophrenia behaviors.","evidence":"Smarca2 knockout mouse behavioral phenotyping, cell-based localization assay for a missense variant, and postmortem brain expression analysis","pmids":["19363039"],"confidence":"Medium","gaps":["Molecular link between BRM loss and behavior unresolved","Causality of risk SNPs in human disease not established"]},{"year":2010,"claim":"Expanded the factor-recruitment model into immune signaling by showing REQ/DPF2 bridges BRM to NF-κB p52 to drive noncanonical NF-κB-dependent BLC/CXCL13 transcription.","evidence":"In vitro binding, ChIP at BLC promoter, and REQ knockdown with reporter assays","pmids":["20460684"],"confidence":"Medium","gaps":["Whether REQ is a dedicated or general BRM adaptor unclear","Broader noncanonical NF-κB target set not defined"]},{"year":2011,"claim":"Defined the molecular basis of cancer-associated BRM silencing as promoter polymorphisms (BRM-741/-1321) creating MEF2 sites that recruit HDAC9-containing complexes, alongside evidence for post-transcriptional suppression.","evidence":"Promoter sequencing, ChIP at polymorphic sites, MEF2D/HDAC9 knockdown; nuclear run-on and RT-PCR with HDAC-inhibitor rescue","pmids":["21478907","16007216"],"confidence":"Medium","gaps":["Relative contribution of transcriptional vs. post-transcriptional silencing not reconciled","Reversibility in patient tumors untested"]},{"year":2011,"claim":"Mechanistically refined the BRM-versus-BRG1 promoter switch at STAT1/GAS elements, showing unphosphorylated STAT1 recruits BRM in an mSin3/HDAC repressive complex that is reversed by p300 acetylation and a switch to BRG1 upon activation.","evidence":"Co-IP of hBRM with STAT1, ChIP at GAS elements, chromatin accessibility and p300 acetylation experiments","pmids":["21079652"],"confidence":"Medium","gaps":["In vitro STAT1–BRM interaction not validated structurally","Generality of the BRM-to-BRG1 switch across IFN targets unknown"]},{"year":2012,"claim":"Connected BRM remodeling to histone-modification crosstalk by showing the BRM bromodomain binds CBP and stimulates H3K27 acetylation while antagonizing H3K27me3.","evidence":"Direct domain-mapped binding, in vitro acetylation assay, mutant histone-mark analysis, and genome-wide ChIP co-localization in Drosophila","pmids":["22493065"],"confidence":"High","gaps":["Conservation of CBP/UTX coupling in human SMARCA2 not directly demonstrated","Whether ATPase activity is required for the acetylation effect untested"]},{"year":2013,"claim":"Added hypoxia signaling and neural progenitor maintenance to BRM's roles, showing BRM/BRG1 act as HIF coactivators and that the Drosophila BRM complex partners with Earmuff and HDAC3 to suppress dedifferentiation.","evidence":"Knockdown/re-expression with ChIP and nucleosome remodeling; co-IP and genetic epistasis in Drosophila","pmids":["23897427","24618901"],"confidence":"Medium","gaps":["BRM-specific vs. redundant contribution at HIF targets not fully separated","Direct BRM–HIF contact not mapped"]},{"year":2013,"claim":"Systematically dissected the enzymes controlling BRM expression and acetylation, mapping HDAC3/HDAC9 to expression, HDAC2 to acetylation, and specific KATs and MAPK signaling as regulators.","evidence":"Selective siRNA knockdown of individual HDACs, overexpression of 21 HATs, and MAPK inhibitor treatment","pmids":["23524580"],"confidence":"Medium","gaps":["Direct vs. indirect enzyme effects on BRM not always distinguished","Integration with promoter-polymorphism silencing not resolved"]},{"year":2014,"claim":"Established the central synthetic-lethal dependency: residual SMARCA2-containing SWI/SNF is essential for proliferation of SMARCA4-mutant cancers, with depletion causing arrest, senescence, and increased H3K9me3.","evidence":"shRNA loss-of-function screens across 165 lines, co-IP of residual complex, xenografts, and H3K9me3 imaging (two concurrent papers)","pmids":["24421395","24520176"],"confidence":"High","gaps":["Which downstream genes mediate the dependency not fully defined","Mechanism of H3K9me3 increase upon SMARCA2 loss unresolved"]},{"year":2017,"claim":"Defined the biochemical targeting logic and druggability of SMARCA2: the bromodomain has modest H3K14ac/DNA binding that is dispensable for global chromatin affinity, and the DNA-dependent ATPase is allosterically inhibitable by small molecules.","evidence":"ITC/SPR binding with mutagenesis and ChIP-seq in BRD-mutant ESCs; ATPase inhibition assays with xenograft validation","pmids":["28706277","30339381"],"confidence":"High","gaps":["What does drive complex targeting if not BRD binding remains open","Allosteric inhibitor selectivity for BRM vs. BRG1 limited"]},{"year":2017,"claim":"Showed PRC2 silences SMARCA2 in SMARCA4-mutant EZH2-inhibitor-sensitive cancers, with EZH2-inhibitor-induced SMARCA2 re-expression driving apoptosis via cathepsin B; also linked BRM to JAK2/STAT3 signaling in pancreatic cancer.","evidence":"EZH2 inhibitor treatment, SMARCA2 re-expression, RNAi, and xenografts; shRNA knockdown with pSTAT3 readout","pmids":["29087303","28602977"],"confidence":"Medium","gaps":["JAK2/STAT3 role rests on single low-confidence knockdown study without direct binding evidence","Direct vs. indirect cathepsin B derepression unresolved"]},{"year":2021,"claim":"Demonstrated a noncanonical SWI/SNF-independent SMARCA2 function and a bromodomain-dependent chromatin-binding requirement: SMARCA2 partners with NSD2 to activate PTP4A3 in myeloma, and BRD inhibition (PFI-3) destabilizes promoter binding needed for myogenic differentiation.","evidence":"SILAC-MS, co-IP, ChIP and H3K36me2 mapping with PFI-3 and xenograft; PFI-3 with ChIP and shRNA in muscle differentiation models","pmids":["33602783","34289068"],"confidence":"High","gaps":["How SMARCA2 functions outside the canonical complex structurally unresolved","Generality of noncanonical NSD2 partnership beyond t(4;14) myeloma untested"]},{"year":2022,"claim":"Achieved therapeutically selective targeting by demonstrating a VHL-recruiting PROTAC (ACBI2) degrades SMARCA2 over SMARCA4 in vivo with antitumor efficacy in SMARCA4-deficient models.","evidence":"Structure-guided PROTAC design with cellular degradation, ex vivo human blood, and in vivo xenograft assays","pmids":["36216795"],"confidence":"High","gaps":["Durability of response and resistance mechanisms not addressed","Off-target neomorphic effects of degradation not evaluated"]},{"year":2024,"claim":"Placed SMARCA2 within a lineage-specification axis, showing SETMAR-driven H3K36 methylation promotes SMARCA2 transcription and SMARCA2 in turn opens PAX8/FOXE1 enhancers to drive thyroid differentiation.","evidence":"SMARCA2 ChIP at enhancers, ATAC-seq, SETMAR knockdown/overexpression, and H3K36 methylation assays","pmids":["38900084"],"confidence":"Medium","gaps":["Whether SMARCA2 acts through canonical SWI/SNF here not established","Direct SMARCA2–enhancer occupancy vs. indirect accessibility change not fully separated"]},{"year":null,"claim":"What determines genome-wide SMARCA2 targeting independent of bromodomain histone/DNA binding, and which downstream gene programs mediate the SMARCA4-mutant synthetic-lethal dependency, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Primary determinant of complex recruitment to specific loci unknown","Effector genes of SMARCA2 dependency in SMARCA4-mutant cancers not defined","Structural basis of noncanonical (complex-independent) SMARCA2 activity unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[6,33]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[31,35]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,35]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[31,26]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,20]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[2,8]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[6,26,31]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,4,35]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,29,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[29,32,36,38]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14,37,39]}],"complexes":["SWI/SNF (BAF) complex"],"partners":["SMARCB1","RB1","E2F1","STAT1","SIN3A","DPF2","NSD2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P51531","full_name":"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2","aliases":["BRG1-associated factor 190B","BAF190B","Probable global transcription activator SNF2L2","Protein brahma homolog","hBRM","SNF2-alpha"],"length_aa":1590,"mass_kda":181.3,"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. Binds DNA non-specifically (PubMed:15075294, PubMed:22952240, PubMed:26601204). 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 (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P51531/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMARCA2","classification":"Not Classified","n_dependent_lines":44,"n_total_lines":1208,"dependency_fraction":0.03642384105960265},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000080503","cell_line_id":"CID001886","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"SMARCB1","stoichiometry":10.0},{"gene":"SMARCE1","stoichiometry":10.0},{"gene":"ARID1A","stoichiometry":0.2},{"gene":"SMARCD2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001886","total_profiled":1310},"omim":[{"mim_id":"619293","title":"BLEPHAROPHIMOSIS-IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME; BIS","url":"https://www.omim.org/entry/619293"},{"mim_id":"618502","title":"BRD4-INTERACTING CHROMATIN REMODELING COMPLEX-ASSOCIATED PROTEIN-LIKE; BICRAL","url":"https://www.omim.org/entry/618502"},{"mim_id":"616114","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 6; CHD6","url":"https://www.omim.org/entry/616114"},{"mim_id":"612458","title":"ACTIN-LIKE 6B; ACTL6B","url":"https://www.omim.org/entry/612458"},{"mim_id":"612409","title":"RNA-BINDING MOTIF PROTEIN 14; RBM14","url":"https://www.omim.org/entry/612409"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SMARCA2"},"hgnc":{"alias_symbol":["BAF190","hSNF2a","hBRM","Sth1p","SNF2LA","BRM","SNF2","SWI2"],"prev_symbol":["SNF2L2"]},"alphafold":{"accession":"P51531","domains":[{"cath_id":"3.40.50.10810","chopping":"707-954","consensus_level":"medium","plddt":84.6524,"start":707,"end":954},{"cath_id":"3.40.50.300","chopping":"962-1179_1232-1290","consensus_level":"high","plddt":84.2544,"start":962,"end":1290},{"cath_id":"1.20.920.10","chopping":"1382-1395_1423-1510","consensus_level":"high","plddt":88.3837,"start":1382,"end":1510}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51531","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51531-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51531-F1-predicted_aligned_error_v6.png","plddt_mean":65.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMARCA2","jax_strain_url":"https://www.jax.org/strain/search?query=SMARCA2"},"sequence":{"accession":"P51531","fasta_url":"https://rest.uniprot.org/uniprotkb/P51531.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51531/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51531"}},"corpus_meta":[{"pmid":"8223438","id":"PMC_8223438","title":"A human homologue of Saccharomyces cerevisiae SNF2/SWI2 and Drosophila brm genes potentiates transcriptional activation by the glucocorticoid receptor.","date":"1993","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8223438","citation_count":544,"is_preprint":false},{"pmid":"24520176","id":"PMC_24520176","title":"Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24520176","citation_count":329,"is_preprint":false},{"pmid":"12620226","id":"PMC_12620226","title":"Transcriptional specificity of human SWI/SNF BRG1 and BRM chromatin remodeling complexes.","date":"2003","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/12620226","citation_count":297,"is_preprint":false},{"pmid":"9326598","id":"PMC_9326598","title":"RB and hbrm cooperate to repress the activation functions of E2F1.","date":"1997","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9326598","citation_count":262,"is_preprint":false},{"pmid":"11238380","id":"PMC_11238380","title":"Purification and characterization of mSin3A-containing Brg1 and hBrm chromatin remodeling complexes.","date":"2001","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/11238380","citation_count":241,"is_preprint":false},{"pmid":"9735357","id":"PMC_9735357","title":"The Drosophila trithorax group proteins BRM, ASH1 and ASH2 are subunits of distinct protein complexes.","date":"1998","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9735357","citation_count":239,"is_preprint":false},{"pmid":"8657132","id":"PMC_8657132","title":"Functional interactions between the hBRM/hBRG1 transcriptional activators and the pRB family of proteins.","date":"1996","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8657132","citation_count":221,"is_preprint":false},{"pmid":"8670841","id":"PMC_8670841","title":"The hbrm and BRG-1 proteins, components of the human SNF/SWI complex, are phosphorylated and excluded from the condensed chromosomes during mitosis.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8670841","citation_count":201,"is_preprint":false},{"pmid":"7579694","id":"PMC_7579694","title":"The Drosophila snr1 and brm proteins are related to yeast SWI/SNF proteins and are components of a large protein complex.","date":"1995","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/7579694","citation_count":199,"is_preprint":false},{"pmid":"24421395","id":"PMC_24421395","title":"Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation.","date":"2014","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24421395","citation_count":196,"is_preprint":false},{"pmid":"30339381","id":"PMC_30339381","title":"Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers.","date":"2018","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30339381","citation_count":194,"is_preprint":false},{"pmid":"22366787","id":"PMC_22366787","title":"Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome.","date":"2012","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22366787","citation_count":192,"is_preprint":false},{"pmid":"26551623","id":"PMC_26551623","title":"SWI/SNF Complex-deficient Undifferentiated/Rhabdoid Carcinomas of the Gastrointestinal Tract: A Series of 13 Cases Highlighting Mutually Exclusive Loss of SMARCA4 and SMARCA2 and Frequent Co-inactivation of SMARCB1 and SMARCA2.","date":"2016","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26551623","citation_count":190,"is_preprint":false},{"pmid":"26356327","id":"PMC_26356327","title":"Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type.","date":"2015","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26356327","citation_count":186,"is_preprint":false},{"pmid":"36216795","id":"PMC_36216795","title":"A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36216795","citation_count":170,"is_preprint":false},{"pmid":"28292935","id":"PMC_28292935","title":"Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models.","date":"2017","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/28292935","citation_count":147,"is_preprint":false},{"pmid":"28038711","id":"PMC_28038711","title":"SMARCA4 and SMARCA2 deficiency in non-small cell lung cancer: immunohistochemical survey of 316 consecutive specimens.","date":"2016","source":"Annals of diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/28038711","citation_count":145,"is_preprint":false},{"pmid":"11850839","id":"PMC_11850839","title":"Concomitant down-regulation of BRM and BRG1 in human tumor cell lines: differential effects on RB-mediated growth arrest vs CD44 expression.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/11850839","citation_count":135,"is_preprint":false},{"pmid":"11274403","id":"PMC_11274403","title":"Analysis of transforming activity of human synovial sarcoma-associated chimeric protein SYT-SSX1 bound to chromatin remodeling factor hBRM/hSNF2 alpha.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11274403","citation_count":134,"is_preprint":false},{"pmid":"15075294","id":"PMC_15075294","title":"TopBP1 recruits Brg1/Brm to repress E2F1-induced apoptosis, a novel pRb-independent and E2F1-specific control for cell survival.","date":"2004","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/15075294","citation_count":127,"is_preprint":false},{"pmid":"7739891","id":"PMC_7739891","title":"A human protein with homology to Saccharomyces cerevisiae SNF5 interacts with the potential helicase hbrm.","date":"1995","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7739891","citation_count":125,"is_preprint":false},{"pmid":"10072425","id":"PMC_10072425","title":"Functional domains of the SYT and SYT-SSX synovial sarcoma translocation proteins and co-localization with the SNF protein BRM in the nucleus.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10072425","citation_count":123,"is_preprint":false},{"pmid":"17546055","id":"PMC_17546055","title":"The reversible epigenetic silencing of BRM: implications for clinical targeted therapy.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17546055","citation_count":122,"is_preprint":false},{"pmid":"23163725","id":"PMC_23163725","title":"Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features.","date":"2013","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/23163725","citation_count":117,"is_preprint":false},{"pmid":"12065415","id":"PMC_12065415","title":"Prohibitin requires Brg-1 and Brm for the repression of E2F and cell growth.","date":"2002","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12065415","citation_count":115,"is_preprint":false},{"pmid":"17075831","id":"PMC_17075831","title":"Aberrant expression of SWI/SNF catalytic subunits BRG1/BRM is associated with tumor development and increased invasiveness in prostate cancers.","date":"2007","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/17075831","citation_count":108,"is_preprint":false},{"pmid":"22493065","id":"PMC_22493065","title":"Histone demethylase UTX and chromatin remodeler BRM bind directly to CBP and modulate acetylation of histone H3 lysine 27.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22493065","citation_count":106,"is_preprint":false},{"pmid":"9799253","id":"PMC_9799253","title":"Sth1p, a Saccharomyces cerevisiae Snf2p/Swi2p homolog, is an essential ATPase in RSC and differs from Snf/Swi in its interactions with histones and chromatin-associated proteins.","date":"1998","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9799253","citation_count":96,"is_preprint":false},{"pmid":"19363039","id":"PMC_19363039","title":"Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19363039","citation_count":94,"is_preprint":false},{"pmid":"16007216","id":"PMC_16007216","title":"The Brm gene suppressed at the post-transcriptional level in various human cell lines is inducible by transient HDAC inhibitor treatment, which exhibits antioncogenic potential.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16007216","citation_count":94,"is_preprint":false},{"pmid":"30722027","id":"PMC_30722027","title":"Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1-associated atypical neurofibromas.","date":"2019","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30722027","citation_count":91,"is_preprint":false},{"pmid":"27656868","id":"PMC_27656868","title":"Loss of expression of SMARCA4 (BRG1), SMARCA2 (BRM) and SMARCB1 (INI1) in undifferentiated carcinoma of the endometrium is not uncommon and is not always associated with rhabdoid morphology.","date":"2016","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/27656868","citation_count":90,"is_preprint":false},{"pmid":"19144648","id":"PMC_19144648","title":"Antagonistic roles for BRM and BRG1 SWI/SNF complexes in differentiation.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19144648","citation_count":87,"is_preprint":false},{"pmid":"18006815","id":"PMC_18006815","title":"Frequent loss of Brm expression in gastric cancer correlates with histologic features and differentiation state.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18006815","citation_count":85,"is_preprint":false},{"pmid":"26729868","id":"PMC_26729868","title":"MicroRNA-276 promotes egg-hatching synchrony by up-regulating brm in locusts.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26729868","citation_count":84,"is_preprint":false},{"pmid":"20457675","id":"PMC_20457675","title":"SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20457675","citation_count":76,"is_preprint":false},{"pmid":"29087303","id":"PMC_29087303","title":"PRC2-mediated repression of SMARCA2 predicts EZH2 inhibitor activity in SWI/SNF mutant tumors.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29087303","citation_count":73,"is_preprint":false},{"pmid":"10330133","id":"PMC_10330133","title":"The activity of mammalian brm/SNF2alpha is dependent on a high-mobility-group protein I/Y-like DNA binding domain.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10330133","citation_count":68,"is_preprint":false},{"pmid":"15722796","id":"PMC_15722796","title":"The expression of the SWI/SNF ATPase subunits BRG1 and BRM in normal human tissues.","date":"2005","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/15722796","citation_count":67,"is_preprint":false},{"pmid":"16135788","id":"PMC_16135788","title":"The BRG1- and hBRM-associated factor BAF57 induces apoptosis by stimulating expression of the cylindromatosis tumor suppressor gene.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16135788","citation_count":65,"is_preprint":false},{"pmid":"28602977","id":"PMC_28602977","title":"BRM/SMARCA2 promotes the proliferation and chemoresistance of pancreatic cancer cells by targeting JAK2/STAT3 signaling.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/28602977","citation_count":62,"is_preprint":false},{"pmid":"28706277","id":"PMC_28706277","title":"DNA binding drives the association of BRG1/hBRM bromodomains with nucleosomes.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28706277","citation_count":60,"is_preprint":false},{"pmid":"15141164","id":"PMC_15141164","title":"BRG1/BRM and prohibitin are required for growth suppression by estrogen antagonists.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15141164","citation_count":60,"is_preprint":false},{"pmid":"26564006","id":"PMC_26564006","title":"Concomitant loss of SMARCA2 and SMARCA4 expression in small cell carcinoma of the ovary, hypercalcemic type.","date":"2015","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/26564006","citation_count":59,"is_preprint":false},{"pmid":"17938176","id":"PMC_17938176","title":"The activity of p53 is differentially regulated by Brm- and Brg1-containing SWI/SNF chromatin remodeling complexes.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17938176","citation_count":59,"is_preprint":false},{"pmid":"24618901","id":"PMC_24618901","title":"The Brm-HDAC3-Erm repressor complex suppresses dedifferentiation in Drosophila type II neuroblast lineages.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/24618901","citation_count":56,"is_preprint":false},{"pmid":"31722744","id":"PMC_31722744","title":"BRM: the core ATPase subunit of SWI/SNF chromatin-remodelling complex-a tumour suppressor or tumour-promoting factor?","date":"2019","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/31722744","citation_count":49,"is_preprint":false},{"pmid":"23524580","id":"PMC_23524580","title":"Identifying targets for the restoration and reactivation of BRM.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23524580","citation_count":47,"is_preprint":false},{"pmid":"20460684","id":"PMC_20460684","title":"Requiem protein links RelB/p52 and the Brm-type SWI/SNF complex in a noncanonical NF-kappaB pathway.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20460684","citation_count":47,"is_preprint":false},{"pmid":"29273066","id":"PMC_29273066","title":"Co-regulation of transcription by BRG1 and BRM, two mutually exclusive SWI/SNF ATPase subunits.","date":"2017","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/29273066","citation_count":47,"is_preprint":false},{"pmid":"31906887","id":"PMC_31906887","title":"Loss of the SWI/SNF-ATPase subunit members SMARCF1 (ARID1A), SMARCA2 (BRM), SMARCA4 (BRG1) and SMARCB1 (INI1) in oesophageal adenocarcinoma.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31906887","citation_count":46,"is_preprint":false},{"pmid":"21478907","id":"PMC_21478907","title":"Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer risk.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21478907","citation_count":45,"is_preprint":false},{"pmid":"11259672","id":"PMC_11259672","title":"The human brm protein is cleaved during apoptosis: the role of cathepsin G.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11259672","citation_count":44,"is_preprint":false},{"pmid":"32694869","id":"PMC_32694869","title":"De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.","date":"2020","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32694869","citation_count":44,"is_preprint":false},{"pmid":"23897427","id":"PMC_23897427","title":"BRG1 and BRM chromatin-remodeling complexes regulate the hypoxia response by acting as coactivators for a subset of hypoxia-inducible transcription factor target genes.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23897427","citation_count":44,"is_preprint":false},{"pmid":"30946989","id":"PMC_30946989","title":"The chromatin remodeling protein BRM regulates the transcription of tight junction proteins: Implication in breast cancer metastasis.","date":"2019","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/30946989","citation_count":43,"is_preprint":false},{"pmid":"19805516","id":"PMC_19805516","title":"Functional specificities of Brm and Brg-1 Swi/Snf ATPases in the feedback regulation of hepatic bile acid biosynthesis.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19805516","citation_count":41,"is_preprint":false},{"pmid":"38437498","id":"PMC_38437498","title":"BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or menin inhibitor.","date":"2024","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/38437498","citation_count":40,"is_preprint":false},{"pmid":"31406271","id":"PMC_31406271","title":"SMARCA2-deficiency confers sensitivity to targeted inhibition of SMARCA4 in esophageal squamous cell carcinoma cell lines.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31406271","citation_count":39,"is_preprint":false},{"pmid":"37523716","id":"PMC_37523716","title":"Discovery of SMD-3040 as a Potent and Selective SMARCA2 PROTAC Degrader with Strong in vivo Antitumor Activity.","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37523716","citation_count":39,"is_preprint":false},{"pmid":"18042045","id":"PMC_18042045","title":"Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54(nrb).","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18042045","citation_count":39,"is_preprint":false},{"pmid":"24913006","id":"PMC_24913006","title":"The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/24913006","citation_count":39,"is_preprint":false},{"pmid":"23088494","id":"PMC_23088494","title":"Alterations of the SWI/SNF chromatin remodelling subunit-BRG1 and BRM in hepatocellular carcinoma.","date":"2012","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/23088494","citation_count":39,"is_preprint":false},{"pmid":"33027072","id":"PMC_33027072","title":"SMARCA4/SMARCA2-deficient Carcinoma of the Esophagus and Gastroesophageal Junction.","date":"2021","source":"The American journal of surgical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/33027072","citation_count":38,"is_preprint":false},{"pmid":"34799403","id":"PMC_34799403","title":"Exquisite Sensitivity to Dual BRG1/BRM ATPase Inhibitors Reveals Broad SWI/SNF Dependencies in Acute Myeloid Leukemia.","date":"2022","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/34799403","citation_count":38,"is_preprint":false},{"pmid":"30447346","id":"PMC_30447346","title":"Inactivation of SMARCA2 by promoter hypermethylation drives lung cancer development.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30447346","citation_count":37,"is_preprint":false},{"pmid":"17855369","id":"PMC_17855369","title":"SWI/SNF chromatin remodeling ATPase Brm regulates the differentiation of early retinal stem cells/progenitors by influencing Brn3b expression and Notch signaling.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17855369","citation_count":37,"is_preprint":false},{"pmid":"19371634","id":"PMC_19371634","title":"Cdx2 and the Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells.","date":"2009","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/19371634","citation_count":33,"is_preprint":false},{"pmid":"28105457","id":"PMC_28105457","title":"Loss of the SWI/SNF ATPase subunits BRM and BRG1 drives lung cancer development.","date":"2016","source":"Oncoscience","url":"https://pubmed.ncbi.nlm.nih.gov/28105457","citation_count":32,"is_preprint":false},{"pmid":"12044884","id":"PMC_12044884","title":"A putative nuclear receptor coactivator (TMF/ARA160) associates with hbrm/hSNF2 alpha and BRG-1/hSNF2 beta and localizes in the Golgi apparatus.","date":"2002","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/12044884","citation_count":31,"is_preprint":false},{"pmid":"27039070","id":"PMC_27039070","title":"BRG1 and BRM SWI/SNF ATPases redundantly maintain cardiomyocyte homeostasis by regulating cardiomyocyte mitophagy and mitochondrial dynamics in vivo.","date":"2016","source":"Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/27039070","citation_count":31,"is_preprint":false},{"pmid":"21079652","id":"PMC_21079652","title":"A switch from hBrm to Brg1 at IFNγ-activated sequences mediates the activation of human genes.","date":"2010","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/21079652","citation_count":30,"is_preprint":false},{"pmid":"30790683","id":"PMC_30790683","title":"BRM transcriptionally regulates miR-302a-3p to target SOCS5/STAT3 signaling axis to potentiate pancreatic cancer metastasis.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30790683","citation_count":30,"is_preprint":false},{"pmid":"25200863","id":"PMC_25200863","title":"Concurrent loss of INI1, PBRM1, and BRM expression in epithelioid sarcoma: implications for the cocontributions of multiple SWI/SNF complex members to pathogenesis.","date":"2014","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25200863","citation_count":30,"is_preprint":false},{"pmid":"25904594","id":"PMC_25904594","title":"SWI/SNF chromatin-remodeling enzymes Brahma-related gene 1 (BRG1) and Brahma (BRM) are dispensable in multiple models of postnatal angiogenesis but are required for vascular integrity in infant mice.","date":"2015","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/25904594","citation_count":30,"is_preprint":false},{"pmid":"31288860","id":"PMC_31288860","title":"New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome.","date":"2019","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/31288860","citation_count":29,"is_preprint":false},{"pmid":"23322154","id":"PMC_23322154","title":"Association of two BRM promoter polymorphisms with head and neck squamous cell carcinoma risk.","date":"2013","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23322154","citation_count":29,"is_preprint":false},{"pmid":"34289068","id":"PMC_34289068","title":"The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34289068","citation_count":29,"is_preprint":false},{"pmid":"30527810","id":"PMC_30527810","title":"Degron mediated BRM/SMARCA2 depletion uncovers novel combination partners for treatment of BRG1/SMARCA4-mutant cancers.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/30527810","citation_count":27,"is_preprint":false},{"pmid":"21564052","id":"PMC_21564052","title":"BRM and BRG1 subunits of the SWI/SNF chromatin remodelling complex are downregulated upon progression of benign skin lesions into invasive tumours.","date":"2011","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/21564052","citation_count":26,"is_preprint":false},{"pmid":"21646426","id":"PMC_21646426","title":"The glucocorticoid receptor and the coregulator Brm selectively modulate each other's occupancy and activity in a gene-specific manner.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21646426","citation_count":26,"is_preprint":false},{"pmid":"34951482","id":"PMC_34951482","title":"Switch/sucrose-non-fermentable (SWI/SNF) complex (SMARCA4, SMARCA2, INI1/SMARCB1)-deficient colorectal carcinomas are strongly associated with microsatellite instability: an incidence study in 4508 colorectal carcinomas.","date":"2022","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/34951482","citation_count":25,"is_preprint":false},{"pmid":"18068534","id":"PMC_18068534","title":"Polycythemia vera transforming to acute myeloid leukemia and complex abnormalities including 9p homogeneously staining region with amplification of MLLT3, JMJD2C, JAK2, and SMARCA2.","date":"2008","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/18068534","citation_count":25,"is_preprint":false},{"pmid":"10320476","id":"PMC_10320476","title":"Nps1/Sth1p, a component of an essential chromatin-remodeling complex of Saccharomyces cerevisiae, is required for the maximal expression of early meiotic genes.","date":"1999","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/10320476","citation_count":24,"is_preprint":false},{"pmid":"18845624","id":"PMC_18845624","title":"Manipulation of SMARCA2 and SMARCA4 transcript levels in porcine embryos differentially alters development and expression of SMARCA1, SOX2, NANOG, and EIF1.","date":"2008","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18845624","citation_count":24,"is_preprint":false},{"pmid":"38180485","id":"PMC_38180485","title":"PROTACs Targeting BRM (SMARCA2) Afford Selective In Vivo Degradation over BRG1 (SMARCA4) and Are Active in BRG1 Mutant Xenograft Tumor Models.","date":"2024","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38180485","citation_count":23,"is_preprint":false},{"pmid":"30478150","id":"PMC_30478150","title":"Targeting of BRM Sensitizes BRG1-Mutant Lung Cancer Cell Lines to Radiotherapy.","date":"2018","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/30478150","citation_count":23,"is_preprint":false},{"pmid":"34124809","id":"PMC_34124809","title":"SMARCA2-NR4A3 is a novel fusion gene of extraskeletal myxoid chondrosarcoma identified by RNA next-generation sequencing.","date":"2021","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34124809","citation_count":23,"is_preprint":false},{"pmid":"25496315","id":"PMC_25496315","title":"Frequent co-inactivation of the SWI/SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhabdoid tumours.","date":"2015","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/25496315","citation_count":22,"is_preprint":false},{"pmid":"24471421","id":"PMC_24471421","title":"Loss of BRM expression is a frequently observed event in poorly differentiated clear cell renal cell carcinoma.","date":"2014","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/24471421","citation_count":22,"is_preprint":false},{"pmid":"29795359","id":"PMC_29795359","title":"Identification of small molecule inhibitors targeting the SMARCA2 bromodomain from a high-throughput screening assay.","date":"2018","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/29795359","citation_count":22,"is_preprint":false},{"pmid":"21811517","id":"PMC_21811517","title":"Complex alternative splicing of the smarca2 gene suggests the importance of smarca2-B variants.","date":"2011","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21811517","citation_count":21,"is_preprint":false},{"pmid":"16707429","id":"PMC_16707429","title":"Role for Brm in cell growth control.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16707429","citation_count":21,"is_preprint":false},{"pmid":"33602783","id":"PMC_33602783","title":"SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic PTP4A3 through Chromatin Remodeling in t(4;14) Multiple Myeloma.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33602783","citation_count":20,"is_preprint":false},{"pmid":"33148612","id":"PMC_33148612","title":"SMARCA2 is regulated by NORFA-miR-29c, a novel pathway that controls granulosa cell apoptosis and is related to female fertility.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/33148612","citation_count":20,"is_preprint":false},{"pmid":"29391557","id":"PMC_29391557","title":"SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29391557","citation_count":20,"is_preprint":false},{"pmid":"38900084","id":"PMC_38900084","title":"SETMAR Facilitates the Differentiation of Thyroid Cancer by Regulating SMARCA2-Mediated Chromatin Remodeling.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38900084","citation_count":19,"is_preprint":false},{"pmid":"39801091","id":"PMC_39801091","title":"Discovery of FHD-286, a First-in-Class, Orally Bioavailable, Allosteric Dual Inhibitor of the Brahma Homologue (BRM) and Brahma-Related Gene 1 (BRG1) ATPase Activity for the Treatment of SWItch/Sucrose Non-Fermentable (SWI/SNF) Dependent Cancers.","date":"2025","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39801091","citation_count":19,"is_preprint":false},{"pmid":"39369768","id":"PMC_39369768","title":"SMARCA4 and SMARCA2 co-deficiency: An uncommon molecular signature defining a subset of rare, aggressive and undifferentiated malignancies associated with defective chromatin remodeling.","date":"2024","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39369768","citation_count":19,"is_preprint":false},{"pmid":"28232072","id":"PMC_28232072","title":"BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility.","date":"2017","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/28232072","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53115,"output_tokens":10351,"usd":0.157305,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":20913,"output_tokens":8137,"usd":0.153995,"stage2_stop_reason":"end_turn"},"total_usd":0.3113,"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\": 1993,\n      \"finding\": \"Human SMARCA2 (hBRM) was identified as a nuclear transcriptional co-activator that cooperates with the glucocorticoid receptor (GR) to activate transcription; cooperation required the DNA-binding domain of GR and two separated regions of hBRM including a helicase-homology domain.\",\n      \"method\": \"Transfection of hBRM into cells lacking endogenous hBRM, followed by transactivation assays with GR reporters; deletion analysis of hBRM domains\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transfection assay with domain-deletion analysis, single lab, two orthogonal approaches (reporter assay + domain mapping)\",\n      \"pmids\": [\"8223438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human SMARCA2 (hBRM) co-immunoprecipitates with hSNF5 (a human SNF5 homologue), and this interaction depends on the conserved SNF5-homology domain of hSNF5, indicating that hBRM and hSNF5 are subunits of a human SWI/SNF complex.\",\n      \"method\": \"Co-immunoprecipitation from cell extracts; interaction mapping with truncation mutants\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP demonstrated, interaction domain mapped, single lab\",\n      \"pmids\": [\"7739891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"During mitosis, SMARCA2 (hBRM) is phosphorylated and excluded from condensed chromosomes; mitotic phosphorylation correlates with decreased affinity for the nuclear structure in early M phase but does not disrupt the hBRM–hSNF5 association. Additionally, the level of hBRM protein is strongly reduced in mitosis.\",\n      \"method\": \"Cell fractionation, Western blot, immunofluorescence across cell cycle stages; co-immunoprecipitation of hBRM with hSNF5\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation plus IF plus co-IP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"8670841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SMARCA2 (hBRM) interacts physically with the pRB family of proteins (pRB, p107, p130) via the LXCXE motif; hBRM requires an intact pRB-binding domain to induce growth arrest, and growth-arrest activity is antagonized by E1A.\",\n      \"method\": \"Yeast two-hybrid, transfection of wild-type and pRB-binding-deficient hBRM mutants into SW13 cells; colony-formation and flat-cell assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional mutagenesis assay, single lab\",\n      \"pmids\": [\"8657132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SMARCA2 (hBRM) cooperates with RB to repress E2F1 transcriptional activity; RB bridges hBRM and E2F1 into a ternary complex in vivo; repression requires the RB-binding domain and the NTP-binding site of hBRM but not its bromodomain. The RB-binding domain of hBRM itself has transcriptional activation potential that RB can repress.\",\n      \"method\": \"Co-immunoprecipitation of E2F1–hBRM–RB complexes; transient transfection repression assays with hBRM deletion mutants; ATPase-dead and bromodomain mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, functional domain mutagenesis, and transcriptional assays in the same study; findings on RB–hBRM cooperation are foundational and mechanistically detailed\",\n      \"pmids\": [\"9326598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A 49-amino-acid AT-hook-like domain in SMARCA2 (brm/SNF2α), rich in lysines and arginines and located downstream of the pRB interaction domain, is required for tethering of brm to chromatin and for cooperation with the glucocorticoid receptor on chromatin-integrated reporters; the LXCXE pRB-binding motif and bromodomain had only moderate effects on these activities.\",\n      \"method\": \"Transfection of deletion mutants into ras-transformed fibroblasts; transactivation assays on integrated vs. episomal reporters; domain-function correlation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple deletion mutants with two orthogonal functional readouts (transformation reversal + chromatin-integrated reporter), single lab\",\n      \"pmids\": [\"10330133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Purified hBRM complex (containing hBRM as its central ATPase) can remodel nucleosomal arrays, increase restriction enzyme accessibility to nucleosomal DNA, and hydrolyze ATP in a DNA-dependent manner; the hBRM complex shows lower remodeling activity than BRG1-containing complexes and is markedly less active on mononucleosomal core particles. The hBRM complex also contains mSin3A and directly interacts with mSin3A in vitro.\",\n      \"method\": \"Epitope-tagged pull-down and fractionation of stable cell lines; in vitro ATPase assay; restriction enzyme accessibility assay on nucleosomal arrays; in vitro binding of hBRM to mSin3A\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution with enzymatic assays (ATPase, restriction enzyme accessibility, nucleosome remodeling) plus direct binding assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"11238380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SYT-SSX1 oncofusion protein physically associates with SMARCA2 (hBRM/hSNF2α); the binding region maps to aa 1–181 of SYT-SSX1 and aa 156–205 of hBRM; overexpression of the hBRM binding region suppressed anchorage-independent growth of SYT-SSX1-expressing cells, indicating that hBRM interaction is functionally required for transformation.\",\n      \"method\": \"Co-immunoprecipitation from expressing cells; domain mapping; soft-agar anchorage-independent growth assay with hBRM fragment overexpression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping and functional rescue experiment, single lab\",\n      \"pmids\": [\"11274403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SMARCA2 (hBRM) is cleaved during apoptosis by cathepsin G (not by caspases-3, -7, or -6); cleavage removes a 20-kDa C-terminal fragment containing the bromodomain and disrupts association of hBRM with the nuclear matrix; cathepsin G redistributes from granules/Golgi to a diffuse nuclear distribution during apoptosis.\",\n      \"method\": \"In vitro cleavage assay with recombinant/purified caspases and cathepsin G; peptide inhibitor of cathepsin G in apoptosis assay; nuclear matrix fractionation of cleaved vs. full-length hBRM\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro cleavage assay identifying cathepsin G, confirmed in vivo with specific peptide inhibitor, functional consequence (nuclear matrix dissociation) measured by fractionation; multiple orthogonal methods\",\n      \"pmids\": [\"11259672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Prohibitin recruits SMARCA2 (Brm) to E2F-responsive promoters; this recruitment is required for prohibitin-mediated repression of E2F transcription and growth suppression; prohibitin-Brm-mediated repression requires RB but the initial association of prohibitin with Brm is RB-independent.\",\n      \"method\": \"Dominant-negative Brm rescue experiment; co-immunoprecipitation of prohibitin with Brm; chromatin immunoprecipitation at E2F-responsive promoters; growth suppression assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and dominant-negative functional assay in one study, single lab\",\n      \"pmids\": [\"12065415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SMARCA2 (BRM) can functionally substitute for BRG1 to restore RB-mediated cell cycle arrest and induce CD44 expression when transfected into BRG1/BRM double-deficient tumor cell lines; however, CD44 expression specifically requires BRM (not BRG1) under physiological conditions in vivo, as demonstrated in BRM-null mice.\",\n      \"method\": \"Transient transfection of BRM into double-deficient tumor cells; analysis of BRM-null mouse tissues for CD44 expression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transfection assay corroborated by in vivo mouse knockout data, single lab\",\n      \"pmids\": [\"11850839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SMARCA2 (BRM) but not BRG1 interacts with two ankyrin repeat proteins (components of Notch signal transduction) through protein-protein interactions unique to BRM, enabling BRM-containing SWI/SNF complexes to be recruited to Notch-responsive promoters during differentiation.\",\n      \"method\": \"Pulldown and co-immunoprecipitation identifying BRM-specific interactors; promoter occupancy analysis comparing BRG1 and BRM complexes\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP/pulldown demonstrating BRM-specific interaction, replicated with two orthogonal methods, single lab\",\n      \"pmids\": [\"12620226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TopBP1 recruits SMARCA2 (Brm)/BRG1 to E2F1-responsive promoters and represses E2F1 (but not E2F2 or E2F3) transcriptional activity through a pRB-independent, Brg1/Brm-dependent mechanism, thereby suppressing E2F1-dependent apoptosis during normal cell growth and DNA damage.\",\n      \"method\": \"Co-immunoprecipitation of TopBP1 with Brm/BRG1; dominant-negative Brm rescue; ChIP at E2F1 promoters; apoptosis assays with Brm knockdown\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and functional dominant-negative experiments, single lab\",\n      \"pmids\": [\"15075294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SMARCA2 (Brm)/BRG1 is required for estrogen antagonist-mediated growth suppression in breast cancer cells through E2F pathway repression; prohibitin recruits Brg1/Brm to promoter-bound E2F via a JNK1 pathway, and their recruitment is induced by estrogen antagonist treatment.\",\n      \"method\": \"Dominant-negative Brm/BRG1 rescue; ChIP at native E2F-responsive promoters; pharmacological JNK1 inhibition experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus dominant-negative functional assays, single lab, multiple methods\",\n      \"pmids\": [\"15141164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SMARCA2 (Brm)-containing SWI/SNF complexes, but not BRG1-containing complexes, are required for active repression of the osteocalcin promoter; BRM complexes bind the repressed osteocalcin promoter and are required for recruitment of the co-repressor HDAC1, whereas BRG1 complexes are required for activation.\",\n      \"method\": \"shRNA depletion of BRM and BRG1 separately; ChIP of BRM/BRG1 and HDAC1 at the osteocalcin promoter; osteoblast differentiation marker analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown combined with ChIP showing direct promoter occupancy and co-repressor recruitment, single lab\",\n      \"pmids\": [\"19144648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Brm (SMARCA2) interacts with SHP nuclear receptor and facilitates SHP-mediated repression of CYP7A1 and auto-repression of SHP in bile acid feedback inhibition; ChIP showed Brm is recruited to both CYP7A1 and SHP promoters following FXR agonist treatment, resulting in inaccessible (repressed) chromatin. This is functionally distinct from BRG1, which interacts with FXR and promotes SHP transactivation.\",\n      \"method\": \"Co-immunoprecipitation of Brm with SHP; ChIP at CYP7A1 and SHP promoters; nucleosome remodeling assay; inducible knockdown/overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and in vitro chromatin accessibility assays in one study, single lab\",\n      \"pmids\": [\"19805516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SMARCA2 (Brm) promotes retinal ganglion cell differentiation by facilitating expression and function of the transcription factor Brn3b and by inhibiting Notch signaling; Brm promotes cell cycle exit during this differentiation process.\",\n      \"method\": \"Perturbation of Brm expression and function in retinal progenitors; analysis of Brn3b expression and Notch signaling markers; cell cycle analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function/overexpression with differentiation phenotype and Notch marker analysis, single lab, single main method\",\n      \"pmids\": [\"17855369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SMARCA2 (Brm) is required for p21 induction by p53 specifically in BRG1-deficient cells; in cells expressing BRG1, BRG1 is the preferentially recruited ATPase for p53-dependent p21 activation. Impaired p21 induction upon BRG1 knockdown is partly due to decreased p53 binding to the p21 promoter.\",\n      \"method\": \"Inducible knockdown of Brm and BRG1 separately; p21/MDM2 mRNA quantification; ChIP of p53 at the p21 promoter\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible knockdown with ChIP evidence for promoter occupancy, single lab, two orthogonal methods\",\n      \"pmids\": [\"17938176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Epigenetic silencing is the primary mechanism of BRM/SMARCA2 loss in cancer: HDAC inhibitors restore BRM expression in BRM/BRG1-deficient cancer cell lines despite the absence of inactivating mutations; HDAC inhibitors also block BRM function (via C-terminal acetylation) when present, but BRM activity is detectable after their removal.\",\n      \"method\": \"Sequencing of BRM in BRM-deficient lines (no mutations found); nuclear run-on and RT-PCR; HDAC inhibitor treatment; BRM activity assays post-inhibitor withdrawal\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutation sequencing plus functional epigenetic rescue experiments, single lab\",\n      \"pmids\": [\"17546055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SMARCA2 (Brm) transactivates the TERT gene and modulates splicing patterns of TERT transcripts; Brm co-localizes with p54(nrb), PSF, and phospho-Ser2 RNA Pol II at TERT exon 7 alternative splicing acceptor sites; Brm knockdown in BRG1-deficient cells reduces TERT expression and increases exon-7/8-excluded (inactive) TERT mRNA, leading to growth arrest.\",\n      \"method\": \"shRNA knockdown of Brm; RT-PCR for TERT splice variants; ChIP showing co-localization of Brm with splicing factors at TERT; co-immunoprecipitation of p54(nrb) with Brm/BRG1\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — shRNA knockdown, ChIP, co-IP, and splice-form analysis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"18042045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SMARCA2 (Brm) knockdown in Smarca2-knockout mice impairs social interaction and prepulse inhibition (schizophrenia-relevant behaviors); a missense risk SNP (rs2296212) reduces nuclear localization efficiency of BRM; intronic risk alleles (rs3763627, rs3793490) are associated with reduced SMARCA2 expression in prefrontal cortex.\",\n      \"method\": \"Smarca2 knockout mouse phenotyping (social interaction, PPI); cell-based nuclear localization assay for missense variant; postmortem brain expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with defined behavioral phenotype plus cell-based localization experiment, single lab\",\n      \"pmids\": [\"19363039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SMARCA2 (Cdx2) and Brm-type SWI/SNF complex cooperatively regulate villin expression in gastrointestinal cells; GST pull-down demonstrated a direct interaction between Cdx2 and several SWI/SNF subunits; ChIP showed co-recruitment of Cdx2 and Brm to the villin promoter HCR-Cdx element.\",\n      \"method\": \"GST pull-down; ChIP; reporter assays; Cdx2 knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction demonstrated by pulldown, confirmed by ChIP at native promoter, single lab\",\n      \"pmids\": [\"19371634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"REQ/DPF2 (requiem) acts as an adaptor that bridges SMARCA2 (Brm)-containing SWI/SNF complex and the NF-κB subunit p52; REQ binds Brm and p52 simultaneously; Brm and REQ are recruited to the BLC/CXCL13 promoter upon lymphotoxin stimulation and are both required for noncanonical NF-κB-dependent BLC transcription.\",\n      \"method\": \"In vitro binding assays (co-IP); ChIP at BLC promoter; REQ knockdown experiments; reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus ChIP plus knockdown, single lab\",\n      \"pmids\": [\"20460684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SMARCA2 (Brm) loss in cancer cells results from post-transcriptional suppression (cells efficiently transcribe BRM but mRNA and pre-mRNA are undetectable), and can be reversed by HDAC inhibitor treatment, demonstrating that the BRM gene is intact and functional in these tumor lines.\",\n      \"method\": \"Nuclear run-on transcription assay; RT-PCR for BRM mRNA and hnRNA; HDAC inhibitor rescue experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear run-on plus RT-PCR orthogonal methods establishing post-transcriptional regulation, single lab\",\n      \"pmids\": [\"16007216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BRM expression is regulated at the transcriptional level by the BRM promoter; two novel BRM promoter insertion polymorphisms (BRM-741 and BRM-1321) create MEF2-binding sites that recruit HDAC-containing complexes, leading to BRM silencing; MEF2D and HDAC9 bind these polymorphic sites (as shown by ChIP) and HDAC9 is overexpressed in BRM-negative cancer cell lines.\",\n      \"method\": \"BRM promoter sequencing; promoter swap ChIP experiments; HDAC9/MEF2D knockdown; ChIP at polymorphic sites\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct promoter binding of regulatory factors, knockdown experiments, and promoter swap approach, single lab\",\n      \"pmids\": [\"21478907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SMARCA2 (hBRM) interacts with STAT1 in vitro; native (unphosphorylated) STAT1 selectively recruits hBRM to IFNγ-activated sequences (GAS) under basal conditions, where hBRM exists in a mSin3/HDAC co-repressor complex maintaining repressed chromatin; upon stress, hBRM is acetylated by p300 and dissociates from the repressor complex, while phospho-STAT1 recruits BRG1 instead — an hBRM-to-BRG1 switch that activates gene expression.\",\n      \"method\": \"Co-IP of hBRM with STAT1; ChIP at GAS elements; chromatin accessibility assays; p300 acetylation experiments\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, and accessibility assays in one study, single lab\",\n      \"pmids\": [\"21079652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila BRM (ortholog of SMARCA2) physically associates with CBP acetyltransferase and the H3K27 demethylase UTX in vivo; BRM binds directly to conserved zinc fingers of CBP via its bromodomain-containing C-terminus; the BRM bromodomain enhances CBP PHD binding to histone H3 and stimulates in vitro acetylation of H3K27; brm mutations reduce H3K27ac and increase H3K27me3 levels.\",\n      \"method\": \"Co-immunoprecipitation and direct binding assays; in vitro acetylation assay with recombinant CBP; brm mutant analysis of histone marks; genome-wide ChIP co-localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding mapped to specific domains, in vitro enzymatic assay (H3K27 acetylation), in vivo co-IP, and genetic phenotype; multiple orthogonal methods in one study\",\n      \"pmids\": [\"22493065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SMARCA2 (BRM) and BRG1 are required as coactivators for a subset of hypoxia-inducible factor (HIF) target genes; HIF1/HIF2 recruit BRG1 complexes to target gene promoters, which promotes nucleosome remodeling in a BRG1 ATPase-dependent manner; BRM depletion in BRG1/BRM-deficient cells reduces hypoxic induction of HIF targets.\",\n      \"method\": \"BRG1/BRM knockdown; re-expression of BRG1/BRM in deficient cells; ChIP at HIF target promoters; nucleosome remodeling assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus re-expression plus ChIP and nucleosome remodeling assay, single lab\",\n      \"pmids\": [\"23897427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC3 and HDAC9 regulate SMARCA2 (BRM) expression, whereas HDAC2 controls BRM acetylation; KAT6A, KAT6B, and KAT7 histone acetyltransferases induce BRM expression, and KAT2B and KAT8 induce its acetylation; the MAP kinase pathway regulates both BRM acetylation and BRM silencing.\",\n      \"method\": \"Selective siRNA knockdown of individual HDACs and overexpression of 21 HATs; MAPK pathway inhibitor treatment; BRM expression and acetylation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — systematic siRNA screen plus overexpression experiments, single lab, replicated across multiple targets\",\n      \"pmids\": [\"23524580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SMARCA2 (BRM) is the catalytic ATPase of a residual SWI/SNF complex that is essential for proliferation of SMARCA4 (BRG1)-mutant cancer cells; loss of SMARCA4 leads to greater incorporation of SMARCA2 into SWI/SNF complexes; SMARCA2 depletion in SMARCA4-mutant cells causes cell cycle arrest, senescence, and increased global H3K9me3.\",\n      \"method\": \"shRNA-based loss-of-function screens across 165 cancer cell lines; co-immunoprecipitation demonstrating residual SMARCA2-containing complex; in vivo xenograft experiments; H3K9me3 immunofluorescence\",\n      \"journal\": \"Molecular and cellular biology / Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large-scale functional screen corroborated by co-IP, in vivo xenograft model, and histone mark analysis; independently replicated across two concurrent papers (PMIDs 24421395 and 24520176)\",\n      \"pmids\": [\"24421395\", \"24520176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila BRM complex (SWI/SNF) associates physically with Earmuff transcription factor and HDAC3 to suppress dedifferentiation of intermediate neural progenitors (INPs) back into neuroblasts; multiple BRM complex components co-immunoprecipitate with Erm; brm and hdac3 genetically interact with erm to prevent type II neuroblast overgrowth.\",\n      \"method\": \"Co-immunoprecipitation of BRM complex subunits with Erm; genetic epistasis (double mutant analysis); brm and hdac3 knockdown phenotyping\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genetic epistasis demonstrating functional cooperation, single lab\",\n      \"pmids\": [\"24618901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The bromodomain (BRD) of SMARCA2 (hBRM) has moderate specificity for H3K14ac; both BRG1 and hBRM BRDs also possess DNA-binding activity via a basic patch surface, and the BRD together with an adjacent AT-hook makes multivalent contacts with AT-rich DNA elements with robust affinity; however, histone-binding activity does not substantially contribute to nucleosome targeting in vitro, and global chromatin affinity of BRG1 in mouse ESCs does not require BRD histone or DNA binding.\",\n      \"method\": \"Binding assays (ITC/SPR) with modified histone peptides and DNA; mutagenesis of basic patch; nucleosome-binding assays; ChIP-seq in BRD-mutant mouse ESCs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding assays with mutagenesis and structural mapping plus in vivo ChIP-seq validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"28706277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SMARCA2 expression is suppressed by PRC2 (EZH2-mediated H3K27me3) in SMARCA4-mutant cancer cells sensitive to EZH2 inhibition; induction of SMARCA2 expression by EZH2 inhibitors is required for apoptosis (but not growth arrest) through derepression of the lysosomal protease cathepsin B; re-expression of SMARCA2 can compensate for SMARCA4 loss and antagonize PRC2 targets.\",\n      \"method\": \"EZH2 inhibitor treatment; SMARCA2 re-expression experiments; RNAi depletion; gene expression analysis; in vivo xenograft models\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection using re-expression and RNAi with in vivo confirmation, single lab\",\n      \"pmids\": [\"29087303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRM/SMARCA2 contains a DNA-dependent ATPase activity that is allosterically inhibitable by small molecules; allosteric BRM/BRG1 dual inhibitors downregulate BRM-dependent gene expression and show antiproliferative activity in BRG1-mutant xenograft models.\",\n      \"method\": \"ATPase inhibition assay; gene expression analysis after inhibitor treatment; oral xenograft tumor model\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic ATPase assay confirmed allosteric inhibition; in vivo functional validation, single lab\",\n      \"pmids\": [\"30339381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BRM/SMARCA2 activates JAK2/STAT3 signaling in pancreatic cancer cells; BRM knockdown reduces STAT3 phosphorylation and transcription of STAT3 target genes, reducing proliferation and increasing gemcitabine sensitivity in vitro and in vivo.\",\n      \"method\": \"shRNA knockdown; Western blot for pSTAT3; RT-PCR for STAT3 targets; xenograft tumor model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — knockdown with pathway marker readout, no direct binding or ChIP, single lab\",\n      \"pmids\": [\"28602977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SMARCA2 (BRM) directly binds to the promoter regions of Claudin genes via interaction with transcription factor Sp1, activates Claudin transcription by modulating histone modifications, and its downregulation drives TGF-β-induced breast cancer cell migration/invasion; TGF-β represses BRM transcription through targeting C/EBPβ.\",\n      \"method\": \"ChIP of BRM at Claudin promoters; co-IP of BRM with Sp1; BRM overexpression/knockdown; migration/invasion assays\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct promoter binding plus co-IP with Sp1 plus functional migration assay, single lab\",\n      \"pmids\": [\"30946989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SMARCA2 interacts with NSD2 in a noncanonical manner independent of the full SWI/SNF complex in t(4;14) multiple myeloma; the NSD2–SMARCA2 complex occupies the PTP4A3 promoter, leading to focal H3K36me2 enrichment and transcriptional activation of PTP4A3; PFI-3 (bromodomain inhibitor of SMARCA2) displaces NSD2 from the PTP4A3 promoter and inhibits myeloma cell viability.\",\n      \"method\": \"SILAC-based mass spectrometry identifying NSD2–SMARCA2 interaction; co-IP; ChIP of NSD2 and SMARCA2 at PTP4A3 promoter; H3K36me2 ChIP; PFI-3 treatment with ChIP; xenograft in vivo\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mass spectrometry identification, reciprocal co-IP, ChIP mapping interaction to PTP4A3 promoter with histone mark, and functional rescue with bromodomain inhibitor; multiple orthogonal methods, in vivo validation\",\n      \"pmids\": [\"33602783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The bromodomains of BRM and BRG1 promote stable chromatin binding at target promoters required for skeletal muscle differentiation; pharmacological inhibition with PFI-3 reduced BRM/BRG1 binding to promoters of myogenic genes, impaired cell cycle exit and muscle-specific gene expression both in vitro and in vivo.\",\n      \"method\": \"PFI-3 bromodomain inhibitor; ChIP of BRM/BRG1 after PFI-3 treatment; BRM/BRG1 shRNA depletion; differentiation marker analysis; in vivo muscle regeneration model\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical inhibition with ChIP validation and in vivo confirmation, single lab\",\n      \"pmids\": [\"34289068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A VHL-recruiting PROTAC (ACBI2) achieves selective degradation of SMARCA2 over SMARCA4 in vivo, demonstrating that structural differences between the two paralogs can be exploited for selective targeted degradation; SMARCA2 degradation shows antitumor efficacy in SMARCA4-deficient cancer models.\",\n      \"method\": \"Structure-guided PROTAC design; cellular degradation assays; ex vivo human whole blood assay; in vivo xenograft model with selective SMARCA2 degradation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-guided design with in vitro degradation assays, ex vivo blood assay, and in vivo xenograft validation; selective over SMARCA4 confirmed\",\n      \"pmids\": [\"36216795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SETMAR methylates dimethylated H3K36 in the SMARCA2 promoter region to promote SMARCA2 transcription; SMARCA2 in turn binds enhancers of thyroid differentiation transcription factors PAX8 and FOXE1 to promote their expression by enhancing chromatin accessibility; METTL3-mediated m6A methylation of SETMAR mRNA regulates this axis.\",\n      \"method\": \"ChIP of SMARCA2 at PAX8/FOXE1 enhancers; ATAC-seq for chromatin accessibility; SETMAR knockdown/overexpression; H3K36 methylation assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and ATAC-seq with functional knockdown, single lab\",\n      \"pmids\": [\"38900084\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMARCA2 (BRM/hBRM) is the DNA-dependent ATPase catalytic subunit of one class of human SWI/SNF (BAF) chromatin-remodeling complexes, where it uses ATP hydrolysis to remodel nucleosomal arrays; it is functionally distinct from its paralog SMARCA4 (BRG1), forming mutually exclusive complexes that differentially recruit transcription factors (e.g., glucocorticoid receptor, SHP, STAT1, Notch components, Cdx2, Sp1) and co-repressors (HDAC1, mSin3A) to specific promoters and enhancers to either activate or repress target genes; it is physically regulated by pRB (which bridges hBRM to E2F1 to repress proliferative genes), cleaved during apoptosis by cathepsin G (releasing it from the nuclear matrix), phosphorylated and excluded from chromosomes during mitosis, and epigenetically silenced in many cancers through HDAC3/HDAC9-dependent promoter mechanisms; in SMARCA4-mutant cancers, residual SMARCA2-containing SWI/SNF complexes become essential for tumor cell survival, establishing a synthetic lethal dependency that is therapeutically exploitable by selective SMARCA2 degraders (PROTACs) or allosteric ATPase inhibitors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMARCA2 (BRM/hBRM) is the DNA-dependent ATPase catalytic subunit of a class of human SWI/SNF chromatin-remodeling complexes that uses ATP hydrolysis to remodel nucleosomal arrays and govern transcription during differentiation, cell-cycle control, and tumor suppression [#6, #1]. Purified hBRM-containing complexes increase restriction-enzyme accessibility on nucleosomal arrays and hydrolyze ATP in a DNA-dependent manner, though they are markedly less active than BRG1/SMARCA4-containing complexes, and they incorporate the co-repressor mSin3A [#6]. Chromatin targeting is multivalent: an AT-hook-like domain tethers BRM to chromatin and is required for cooperation with the glucocorticoid receptor, while the bromodomain shows modest H3K14ac preference and, with the adjacent AT-hook, binds AT-rich DNA, contributing to stable promoter occupancy [#5, #31]. BRM acts as a cofactor that is recruited by, and confers specificity through, partners distinct from those used by BRG1 — including the pRB family, which bridges BRM to E2F1 to repress proliferative genes and impose growth arrest, and a series of sequence-specific factors (SHP, STAT1, Notch-associated ankyrin proteins, Cdx2, Sp1, NF-\\u03baB p52 via the REQ/DPF2 adaptor) that direct it to specific promoters and enhancers for either activation or repression, frequently via recruitment of co-repressors such as HDAC1 [#4, #3, #15, #25, #21, #22, #14, #35]. BRM activity and abundance are regulated post-translationally and epigenetically — it is cleaved during apoptosis by cathepsin G to release it from the nuclear matrix, phosphorylated and excluded from chromosomes during mitosis, and silenced in many cancers through HDAC/MEF2-dependent promoter polymorphisms and PRC2-mediated H3K27me3 despite an intact, mutation-free gene [#8, #2, #24, #32, #23]. In SMARCA4-mutant cancers, residual SMARCA2-containing SWI/SNF complexes become essential for proliferation, defining a synthetic-lethal dependency exploitable by selective SMARCA2 PROTAC degraders and allosteric ATPase inhibitors [#29, #38, #33]. Genetic variants reducing SMARCA2 nuclear localization and expression are associated with schizophrenia-relevant behavioral phenotypes [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established SMARCA2 as a nuclear transcriptional co-activator, answering whether the human BRM protein had a transcriptional function and revealing it requires both a helicase-homology domain and partner DNA-binding factors.\",\n      \"evidence\": \"Transfection of hBRM into hBRM-deficient cells with GR reporter transactivation and domain-deletion mapping\",\n      \"pmids\": [\"8223438\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish enzymatic mechanism or complex membership\", \"Cooperation with GR shown on reporters, not native loci\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Placed hBRM within a multi-subunit human SWI/SNF complex by demonstrating physical association with hSNF5, answering whether the human protein assembles into a complex like its yeast counterpart.\",\n      \"evidence\": \"Co-immunoprecipitation with truncation-mutant interaction mapping\",\n      \"pmids\": [\"7739891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full complex composition not defined\", \"No demonstration of remodeling activity\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined cell-cycle regulation of BRM, showing it is phosphorylated, excluded from condensed chromosomes, and reduced in abundance during mitosis without disrupting the hBRM\\u2013hSNF5 interaction.\",\n      \"evidence\": \"Cell fractionation, immunofluorescence across cell-cycle stages, and co-IP\",\n      \"pmids\": [\"8670841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible mitotic kinase not identified\", \"Functional consequence of chromosomal exclusion not established\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Connected BRM to growth control by showing LXCXE-mediated interaction with the pRB family is required for BRM-induced growth arrest, antagonized by E1A.\",\n      \"evidence\": \"Yeast two-hybrid plus colony-formation/flat-cell assays with pRB-binding-deficient mutants\",\n      \"pmids\": [\"8657132\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target genes of the arrest program not defined\", \"Mechanism of pRB-BRM cooperation at promoters not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Resolved the mechanism of BRM-mediated repression by demonstrating RB bridges BRM and E2F1 into a ternary complex requiring the RB-binding domain and ATPase site but not the bromodomain.\",\n      \"evidence\": \"Reciprocal co-IP of E2F1\\u2013hBRM\\u2013RB, transcriptional repression assays, and ATPase-dead/bromodomain mutants\",\n      \"pmids\": [\"9326598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which E2F target genes are physiologically controlled not fully mapped\", \"In vitro repression vs. native promoter occupancy distinction limited\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified the AT-hook-like domain as the chromatin-tethering module required for cooperation with GR on integrated (chromatinized) reporters, distinguishing chromatin targeting from pRB-binding and bromodomain functions.\",\n      \"evidence\": \"Deletion-mutant transfection with integrated vs. episomal reporter transactivation in ras-transformed fibroblasts\",\n      \"pmids\": [\"10330133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DNA/chromatin binding of the AT-hook not biochemically resolved here\", \"Genome-wide targeting role untested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Provided direct biochemical proof that the hBRM complex is a bona fide ATP-dependent remodeler, establishing DNA-dependent ATPase and nucleosome-remodeling activity and lower activity than BRG1 complexes.\",\n      \"evidence\": \"Purified complex with in vitro ATPase, restriction-enzyme accessibility, nucleosome-array remodeling assays, and mSin3A binding\",\n      \"pmids\": [\"11238380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of lower activity vs. BRG1 not determined\", \"Physiological significance of mSin3A association not tested in cells\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked BRM to oncogenesis and to apoptotic regulation through two studies: SYT-SSX1 fusion requires BRM binding for transformation, and BRM is cleaved by cathepsin G during apoptosis to release it from the nuclear matrix.\",\n      \"evidence\": \"Co-IP/domain mapping with soft-agar assays; in vitro cathepsin G cleavage with inhibitor and nuclear-matrix fractionation\",\n      \"pmids\": [\"11274403\", \"11259672\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of nuclear-matrix release for transcription not measured\", \"Whether cathepsin G cleavage is a general apoptotic event unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated factor-directed recruitment of BRM to E2F promoters via prohibitin and showed BRM can functionally substitute for BRG1 in RB-mediated arrest while having a unique requirement for CD44 expression.\",\n      \"evidence\": \"Co-IP, ChIP at E2F promoters, dominant-negative rescue; transfection into double-deficient cells and BRM-null mouse tissue analysis\",\n      \"pmids\": [\"12065415\", \"11850839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why some targets require BRM specifically not mechanistically explained\", \"Prohibitin\\u2013BRM interaction interface not mapped\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the paralog-specificity principle by showing BRM, but not BRG1, uses unique protein interactions (Notch-associated ankyrin repeat proteins) to occupy distinct promoters during differentiation.\",\n      \"evidence\": \"Pulldown/co-IP of BRM-specific interactors and promoter occupancy comparison\",\n      \"pmids\": [\"12620226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of BRM-specific interaction not defined\", \"Breadth of BRM-exclusive interactome unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended BRM's E2F1-repressive role to a pRB-independent, TopBP1-recruited mechanism that suppresses E2F1-dependent apoptosis, broadening the recruitment routes that target BRM/BRG1 to E2F promoters.\",\n      \"evidence\": \"Co-IP of TopBP1, ChIP at E2F1 promoters, dominant-negative rescue, apoptosis assays; ChIP plus JNK1 inhibition in breast cancer cells\",\n      \"pmids\": [\"15075294\", \"15141164\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for E2F1 over E2F2/3 mechanistically unexplained\", \"Direct vs. indirect TopBP1\\u2013BRM contact not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Consolidated BRM as a context-specific activator or repressor through distinct partners (SHP, p53/p21, osteocalcin/HDAC1, Brn3b) and identified epigenetic silencing as the primary route of BRM loss in cancer.\",\n      \"evidence\": \"Separate shRNA/inducible knockdown, ChIP, and chromatin accessibility studies; BRM sequencing showing no mutations and HDAC-inhibitor rescue\",\n      \"pmids\": [\"19805516\", \"17938176\", \"19144648\", \"17855369\", \"17546055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Rules governing activation vs. repression at a given locus not unified\", \"RGC differentiation role rests on single low-confidence study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked BRM to co-transcriptional RNA processing by showing it transactivates TERT and modulates TERT splicing in association with p54(nrb)/PSF and elongating Pol II.\",\n      \"evidence\": \"shRNA knockdown, splice-variant RT-PCR, ChIP co-localization, and co-IP of splicing factors\",\n      \"pmids\": [\"18042045\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct role of remodeling vs. splicing-factor scaffolding not separated\", \"Generality across other genes untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected SMARCA2 to neurodevelopmental phenotypes and identified regulatory and missense variants affecting expression and nuclear localization relevant to schizophrenia behaviors.\",\n      \"evidence\": \"Smarca2 knockout mouse behavioral phenotyping, cell-based localization assay for a missense variant, and postmortem brain expression analysis\",\n      \"pmids\": [\"19363039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between BRM loss and behavior unresolved\", \"Causality of risk SNPs in human disease not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Expanded the factor-recruitment model into immune signaling by showing REQ/DPF2 bridges BRM to NF-\\u03baB p52 to drive noncanonical NF-\\u03baB-dependent BLC/CXCL13 transcription.\",\n      \"evidence\": \"In vitro binding, ChIP at BLC promoter, and REQ knockdown with reporter assays\",\n      \"pmids\": [\"20460684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether REQ is a dedicated or general BRM adaptor unclear\", \"Broader noncanonical NF-\\u03baB target set not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the molecular basis of cancer-associated BRM silencing as promoter polymorphisms (BRM-741/-1321) creating MEF2 sites that recruit HDAC9-containing complexes, alongside evidence for post-transcriptional suppression.\",\n      \"evidence\": \"Promoter sequencing, ChIP at polymorphic sites, MEF2D/HDAC9 knockdown; nuclear run-on and RT-PCR with HDAC-inhibitor rescue\",\n      \"pmids\": [\"21478907\", \"16007216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of transcriptional vs. post-transcriptional silencing not reconciled\", \"Reversibility in patient tumors untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mechanistically refined the BRM-versus-BRG1 promoter switch at STAT1/GAS elements, showing unphosphorylated STAT1 recruits BRM in an mSin3/HDAC repressive complex that is reversed by p300 acetylation and a switch to BRG1 upon activation.\",\n      \"evidence\": \"Co-IP of hBRM with STAT1, ChIP at GAS elements, chromatin accessibility and p300 acetylation experiments\",\n      \"pmids\": [\"21079652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro STAT1\\u2013BRM interaction not validated structurally\", \"Generality of the BRM-to-BRG1 switch across IFN targets unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected BRM remodeling to histone-modification crosstalk by showing the BRM bromodomain binds CBP and stimulates H3K27 acetylation while antagonizing H3K27me3.\",\n      \"evidence\": \"Direct domain-mapped binding, in vitro acetylation assay, mutant histone-mark analysis, and genome-wide ChIP co-localization in Drosophila\",\n      \"pmids\": [\"22493065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of CBP/UTX coupling in human SMARCA2 not directly demonstrated\", \"Whether ATPase activity is required for the acetylation effect untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Added hypoxia signaling and neural progenitor maintenance to BRM's roles, showing BRM/BRG1 act as HIF coactivators and that the Drosophila BRM complex partners with Earmuff and HDAC3 to suppress dedifferentiation.\",\n      \"evidence\": \"Knockdown/re-expression with ChIP and nucleosome remodeling; co-IP and genetic epistasis in Drosophila\",\n      \"pmids\": [\"23897427\", \"24618901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"BRM-specific vs. redundant contribution at HIF targets not fully separated\", \"Direct BRM\\u2013HIF contact not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Systematically dissected the enzymes controlling BRM expression and acetylation, mapping HDAC3/HDAC9 to expression, HDAC2 to acetylation, and specific KATs and MAPK signaling as regulators.\",\n      \"evidence\": \"Selective siRNA knockdown of individual HDACs, overexpression of 21 HATs, and MAPK inhibitor treatment\",\n      \"pmids\": [\"23524580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect enzyme effects on BRM not always distinguished\", \"Integration with promoter-polymorphism silencing not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the central synthetic-lethal dependency: residual SMARCA2-containing SWI/SNF is essential for proliferation of SMARCA4-mutant cancers, with depletion causing arrest, senescence, and increased H3K9me3.\",\n      \"evidence\": \"shRNA loss-of-function screens across 165 lines, co-IP of residual complex, xenografts, and H3K9me3 imaging (two concurrent papers)\",\n      \"pmids\": [\"24421395\", \"24520176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which downstream genes mediate the dependency not fully defined\", \"Mechanism of H3K9me3 increase upon SMARCA2 loss unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the biochemical targeting logic and druggability of SMARCA2: the bromodomain has modest H3K14ac/DNA binding that is dispensable for global chromatin affinity, and the DNA-dependent ATPase is allosterically inhibitable by small molecules.\",\n      \"evidence\": \"ITC/SPR binding with mutagenesis and ChIP-seq in BRD-mutant ESCs; ATPase inhibition assays with xenograft validation\",\n      \"pmids\": [\"28706277\", \"30339381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What does drive complex targeting if not BRD binding remains open\", \"Allosteric inhibitor selectivity for BRM vs. BRG1 limited\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed PRC2 silences SMARCA2 in SMARCA4-mutant EZH2-inhibitor-sensitive cancers, with EZH2-inhibitor-induced SMARCA2 re-expression driving apoptosis via cathepsin B; also linked BRM to JAK2/STAT3 signaling in pancreatic cancer.\",\n      \"evidence\": \"EZH2 inhibitor treatment, SMARCA2 re-expression, RNAi, and xenografts; shRNA knockdown with pSTAT3 readout\",\n      \"pmids\": [\"29087303\", \"28602977\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAK2/STAT3 role rests on single low-confidence knockdown study without direct binding evidence\", \"Direct vs. indirect cathepsin B derepression unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a noncanonical SWI/SNF-independent SMARCA2 function and a bromodomain-dependent chromatin-binding requirement: SMARCA2 partners with NSD2 to activate PTP4A3 in myeloma, and BRD inhibition (PFI-3) destabilizes promoter binding needed for myogenic differentiation.\",\n      \"evidence\": \"SILAC-MS, co-IP, ChIP and H3K36me2 mapping with PFI-3 and xenograft; PFI-3 with ChIP and shRNA in muscle differentiation models\",\n      \"pmids\": [\"33602783\", \"34289068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SMARCA2 functions outside the canonical complex structurally unresolved\", \"Generality of noncanonical NSD2 partnership beyond t(4;14) myeloma untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Achieved therapeutically selective targeting by demonstrating a VHL-recruiting PROTAC (ACBI2) degrades SMARCA2 over SMARCA4 in vivo with antitumor efficacy in SMARCA4-deficient models.\",\n      \"evidence\": \"Structure-guided PROTAC design with cellular degradation, ex vivo human blood, and in vivo xenograft assays\",\n      \"pmids\": [\"36216795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability of response and resistance mechanisms not addressed\", \"Off-target neomorphic effects of degradation not evaluated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed SMARCA2 within a lineage-specification axis, showing SETMAR-driven H3K36 methylation promotes SMARCA2 transcription and SMARCA2 in turn opens PAX8/FOXE1 enhancers to drive thyroid differentiation.\",\n      \"evidence\": \"SMARCA2 ChIP at enhancers, ATAC-seq, SETMAR knockdown/overexpression, and H3K36 methylation assays\",\n      \"pmids\": [\"38900084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SMARCA2 acts through canonical SWI/SNF here not established\", \"Direct SMARCA2\\u2013enhancer occupancy vs. indirect accessibility change not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"What determines genome-wide SMARCA2 targeting independent of bromodomain histone/DNA binding, and which downstream gene programs mediate the SMARCA4-mutant synthetic-lethal dependency, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary determinant of complex recruitment to specific loci unknown\", \"Effector genes of SMARCA2 dependency in SMARCA4-mutant cancers not defined\", \"Structural basis of noncanonical (complex-independent) SMARCA2 activity unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [6, 33]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [31, 35]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 35]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [31, 26]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 20]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [6, 26, 31]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 4, 35]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 29, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [29, 32, 36, 38]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14, 37, 39]}\n    ],\n    \"complexes\": [\"SWI/SNF (BAF) complex\"],\n    \"partners\": [\"SMARCB1\", \"RB1\", \"E2F1\", \"STAT1\", \"SIN3A\", \"DPF2\", \"NSD2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}