{"gene":"SMARCE1","run_date":"2026-06-10T07:46:35","timeline":{"discoveries":[{"year":2022,"finding":"SMARCE1 plays a structural role in selectively stabilizing the canonical BAF (cBAF) complex core-ATPase module interaction. In SMARCE1-deficient clear cell meningioma cells, cBAF complexes fail to stabilize on chromatin, reducing enhancer accessibility, and residual core module components increase formation of BRD9-containing non-canonical BAF (ncBAF) complexes. This combined attenuation of cBAF and increased ncBAF activity generates the CCM-specific gene expression signature, and SMARCE1-deficient cells exhibit heightened sensitivity to small-molecule ncBAF inhibition.","method":"Biochemical fractionation, chromatin accessibility assays (ATAC-seq), small-molecule inhibition, genetic loss-of-function in CCM cell lines and patient tumors","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical fractionation, chromatin accessibility, genetic rescue, pharmacological inhibition) in a single rigorous study with direct functional validation","pmids":["35681054"],"is_preprint":false},{"year":2005,"finding":"BAF57/SMARCE1 directly binds to the androgen receptor (AR) and is recruited to endogenous AR target loci upon ligand activation. Loss of BAF57 severely compromises AR-dependent transactivation in prostatic adenocarcinoma cells, and this activity requires SWI/SNF ATPase function. Both BAF57 and BRM are required for AR-dependent proliferation of prostate cancer cells.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, reporter assays, cell proliferation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP on endogenous targets, rescue experiments, replicated by subsequent studies","pmids":["15743818"],"is_preprint":false},{"year":2008,"finding":"BAF57/SMARCE1 is recruited to the AR DNA-binding domain/hinge region concomitant with receptor activation. A BAF57-derived inhibitory peptide (BIPep) blocks AR residence on chromatin and AR-dependent gene activation, inhibiting androgen-dependent prostate cancer cell proliferation in AR-positive cells.","method":"ChIP, peptide inhibitor functional assays, cell proliferation assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP mapping of recruitment domain, peptide-based functional blockade, multiple cell line validation","pmids":["18559499"],"is_preprint":false},{"year":2006,"finding":"BAF57/SMARCE1 is required for ERα-mediated transcription and estrogen-stimulated proliferation in breast cancer cells. Structure-function analysis defined a region within the ERα hinge domain as essential for BAF57 recruitment. BAF57 is an ER subtype-selective modulator, specifically regulating ERα- but not ERβ-mediated transcription.","method":"siRNA knockdown, reporter assays, structure-function deletion analysis, cell proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (knockdown, mutagenesis/deletion mapping, proliferation assays), replicated across constructs","pmids":["16769725"],"is_preprint":false},{"year":2005,"finding":"Exogenous expression of BAF57/SMARCE1 or certain deletion mutants triggers proteasome-dependent degradation of endogenous BAF57. The protein levels of BAF155 and BAF170 dictate the maximum cellular amount of BAF57 through direct protein-protein interactions; specific interacting domains between BAF57 and BAF155 were mapped.","method":"Exogenous expression, proteasome inhibitor experiments, co-immunoprecipitation, deletion mapping","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (domain mapping, proteasome inhibition, Co-IP) demonstrating the regulatory mechanism","pmids":["16199878"],"is_preprint":false},{"year":2005,"finding":"Re-expression of BAF57/SMARCE1 in BT549 breast carcinoma cells (which lack endogenous BAF57) induces growth arrest, contact inhibition, and apoptosis. ChIP analysis identified CYLD (familial cylindromatosis tumor suppressor) as a direct transcriptional target of BAF57. siRNA suppression of CYLD inhibited BAF57-mediated cell death.","method":"Stable cell line re-expression, growth assays, microarray, ChIP, siRNA knockdown","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirming direct target, siRNA rescue epistasis, multiple phenotypic readouts","pmids":["16135788"],"is_preprint":false},{"year":2010,"finding":"Depletion of BAF57 from the SWI/SNF complex causes significant co-depletion of BAF180 from the complex without reducing total cellular BAF180 levels, establishing BAF57 as required for maintaining proper SWI/SNF subunit composition. BAF57 knockdown causes G2-M accumulation, inhibition of colony formation, and transcriptional misregulation of cell cycle genes involved in late G2.","method":"SILAC-based quantitative proteomics of affinity-purified SWI/SNF, shRNA knockdown, cell cycle analysis, colony formation assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — quantitative proteomics (SILAC) plus multiple functional assays confirming complex composition and cell cycle role","pmids":["20460533"],"is_preprint":false},{"year":2017,"finding":"SMARCE1 drives invasion of ductal carcinoma in situ (DCIS) by regulating expression of secreted proteases that degrade basement membrane. SMARCE1 forms a SWI/SNF-independent complex with transcription factor ILF3 to promote invasion. SMARCE1 is also required for metastasis in vivo in xenograft models.","method":"siRNA/shRNA knockdown, primary human mammary tissue invasion assay, in vivo xenograft metastasis, co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifying novel ILF3 complex, in vivo metastasis model, primary tissue functional assay","pmids":["28377514"],"is_preprint":false},{"year":2016,"finding":"SMARCE1 interacts with and potentiates the transcriptional activity of HIF1A in response to loss of attachment (anoikis conditions). This leads to rapid PTK2 (FAK) activation and downstream ERK/AKT pathway activation, suppressing pro-apoptotic BIM. Both HIF1A and PTK2 are required for SMARCE1-mediated protection against anoikis and lung metastasis in vivo.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, xenograft metastasis model, ERK/AKT signaling assays","journal":"Breast cancer research : BCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ChIP, in vivo xenograft, multiple epistasis experiments with HIF1A and PTK2","pmids":["27495308"],"is_preprint":false},{"year":2015,"finding":"SMARCE1 binds to regulatory regions of the EGFR locus and suppresses EGFR transcription, in part through regulating expression of Polycomb Repressive Complex component CBX2. SMARCE1 loss induces EGFR expression and confers resistance to MET and ALK inhibitors in non-small cell lung cancers.","method":"ChIP, siRNA knockdown, drug resistance assays, gene expression analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP at EGFR locus, CBX2 mechanism, pharmacological validation with EGFR inhibitor rescue","pmids":["25656847"],"is_preprint":false},{"year":2013,"finding":"Heterozygous germline loss-of-function mutations in SMARCE1 cause familial multiple spinal meningiomas. Tumors from affected individuals show loss of SMARCE1 protein expression, consistent with a tumor suppressor two-hit mechanism. All mutation-associated tumors were of clear-cell histological subtype.","method":"Exome sequencing, Sanger sequencing, immunohistochemistry for SMARCE1 protein loss","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — exome discovery replicated in additional cases, IHC confirmation of protein loss, consistent two-hit pattern","pmids":["23377182"],"is_preprint":false},{"year":2013,"finding":"Aberrant elevated BAF57/SMARCE1 expression in prostate cancer circumvents androgen-mediated signaling, induces α2 integrin upregulation via altered SWI/SNF occupancy at the α2 integrin locus, and confers a pro-metastatic migratory advantage that is attenuated by anti-α2 integrin antibody blockade.","method":"Gene expression analysis, ChIP at α2 integrin locus, cell migration assays, antibody blockade, immunohistochemistry of human specimens","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and functional migration assay, single lab study","pmids":["23493350"],"is_preprint":false},{"year":2009,"finding":"Neuron-specific alternative splicing of BAF57/SMARCE1 exons II, III, and IV produces N-terminally truncated isoforms (N-BAF57s) predominantly expressed in the nervous system. These isoforms associate with Brg1, Brm, BAF155, and BAF170 into functional SWI/SNF complexes, and their overexpression in non-neural cells affects expression of NRSE-containing genes.","method":"RT-PCR, biochemical fractionation, co-immunoprecipitation, transient overexpression","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and fractionation confirming complex assembly, functional gene expression effect, single lab","pmids":["19245665"],"is_preprint":false},{"year":2020,"finding":"BAF57/SMARCE1 is upregulated in a Parkinson's disease model (6-OHDA) and is required for induction of the pro-apoptotic protein PUMA by FoxO3a in dopaminergic neurons. BAF57 is necessary for FoxO3a-mediated transcriptional activation of PUMA, linking SWI/SNF chromatin remodeling to neuronal apoptosis in this context.","method":"siRNA knockdown, qPCR, Western blot, primary neuronal cultures and PC12 cells, in vivo 6-OHDA rat model","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function with defined phenotypic readout (PUMA induction, neuronal death), in vitro and in vivo, single lab","pmids":["31971251"],"is_preprint":false},{"year":2022,"finding":"SMARCE1 directly interacts with MYCN and is required for MYCN-mediated transcriptional activation of downstream target genes (PLK1, ODC1, E2F2) in neuroblastoma cells. Conversely, MYCN directly regulates SMARCE1 transcription through binding to a non-canonical E-box in the SMARCE1 promoter, creating a positive feedback loop.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, overexpression rescue, promoter reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP at target loci, rescue experiments; single lab study","pmids":["35978151"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of the HMG domain of BAF57/SMARCE1 was solved at 2.55 Å resolution. The domain consists of three α-helices in an L-shaped form stabilized by a hydrophobic core. Fluorescence quenching assays showed that BAF57-HMG binds four-way junction (4WJ) DNA with an affinity of ~296 nM, and the 4WJ DNA-binding site was identified structurally.","method":"X-ray crystallography, fluorescence quenching binding assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at 2.55 Å with biochemical binding validation; single lab but Tier 1 method","pmids":["33010889"],"is_preprint":false},{"year":2022,"finding":"The assembly mechanism of BAF core subunits was investigated; SMARCE1 (residues 210-284) interacts with SMARCC1 (residues 862-966). Binary, ternary, and tetrameric complexes of SMARCC1/SMARCD1/SMARCB1/SMARCE1 were reconstituted, and crystals of the SMARCC1(883-966)/SMARCE1(210-284) binary complex were obtained with diffraction data to 3.2 Å.","method":"Co-expression and co-purification, crystallography (3.2 Å), pulldown mapping of interacting fragments","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystallographic data obtained but resolution and functional validation limited; single lab","pmids":["35158202"],"is_preprint":false},{"year":2024,"finding":"Disruption of Smarce1 in mouse embryonic stem cells (ESCs) causes dissociation of other SWI/SNF complex components, decreased nucleosome stability (loosened histone-DNA binding), and ectopic genomic redistribution of the SWI/SNF complex as shown by sucrose gradient sedimentation. Unstable nucleosomes persist during differentiation, impairing heterochromatin formation required for normal ESC differentiation.","method":"Homozygous mutant ESC generation, sucrose gradient sedimentation, histone binding assays, differentiation assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods (fractionation, nucleosome stability assay, complex integrity) plus functional differentiation phenotype; single lab","pmids":["38357971"],"is_preprint":false},{"year":2018,"finding":"Loss of smarce1 in zebrafish causes defects in endocardial development from early stages, leading to a misshapen heart tube and increased expression of cardiac transcription factors. Smarce1 binds to cis-regulatory regions of the gata5 gene and is necessary for recruitment of the BAF complex to these regions.","method":"CRISPR/Cas9 knockout zebrafish, gene expression analysis, ChIP at gata5 locus","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR loss-of-function with defined developmental phenotype and ChIP demonstrating direct genomic occupancy; single lab","pmids":["30337622"],"is_preprint":false},{"year":2025,"finding":"Loss of smarce1 function in zebrafish (ENU mutant and morpholino knockdown) causes ventricular cardiomyocyte hyperproliferation without hypertrophy, while myocardium-specific overexpression reduces CM proliferation. Exogenous smarce1 mRNA injection rescues the hyperproliferative phenotype, establishing smarce1 as a cell-autonomous negative regulator of CM proliferation during heart development.","method":"ENU mutagenesis screen, morpholino knockdown, mRNA rescue, Tet-On myocardium-specific overexpression, EdU labeling, immunofluorescence","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic approaches (mutant, morphant, rescue, overexpression) all converging on same phenotype with quantitative CM proliferation readout","pmids":["40950410"],"is_preprint":false},{"year":2026,"finding":"Smarce1 deficiency in zebrafish enhances cardiomyocyte proliferative activity by modulating cell cycle dynamics and chromatin accessibility. Integrative transcriptomic and epigenomic analysis revealed that Smarce1 regulates Stat3 signaling components. Genetic and pharmacological modulation of Stat3 confirmed its functional contribution to Smarce1-dependent CM proliferation, establishing a Smarce1-Stat3 axis in cardiac growth.","method":"RNA-seq, single-cell RNA-seq, ATAC-seq, genetic Smarce1 loss-of-function, pharmacological Stat3 modulation","journal":"Biological research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multi-omics (RNA-seq, scRNA-seq, ATAC-seq) plus orthogonal genetic and pharmacological epistasis; single lab","pmids":["41808150"],"is_preprint":false},{"year":2007,"finding":"SMARCE1 binds directly to an HBV core promoter containing naturally occurring deletions, as demonstrated by gel shift assay and DNA-protein array. SMARCE1 overexpression represses HBV replication, demonstrating a direct functional role as a host repressor of HBV.","method":"Gel shift assay (EMSA), DNA-protein array, overexpression functional assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — EMSA and DNA-protein array with functional validation; single lab","pmids":["17669635"],"is_preprint":false},{"year":2021,"finding":"BAF57/SMARCE1 interacts with splicing factor SRSF1 (as shown by co-immunoprecipitation), and mechanical stress-induced alternative splicing of cyclin D1 (producing cyclin D1b isoform) is regulated by BAF57/SMARCE1 in osteoblast and keratinocyte cell lines.","method":"Co-immunoprecipitation, RT-PCR, overexpression and siRNA knockdown, cyclic stretch mechanical stimulation","journal":"Genes","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP plus knockdown/overexpression data; partial mechanistic follow-up; single lab","pmids":["33670012"],"is_preprint":false},{"year":2018,"finding":"A nucleus-transducible BAF57 fragment lacking proline-rich and HMG domains (ntBAF57-ΔPH) disrupts the interaction between BAF155 and BAF57, leading to proteasomal degradation of endogenous BAF57 and BAF155, and suppresses T cell activation. In vivo administration enhanced survival in sepsis-induced mice.","method":"Protein transduction into CD4+ T cells, co-immunoprecipitation, gene expression analysis, in vivo sepsis model","journal":"International journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP confirming disrupted BAF155-BAF57 interaction, functional T cell and in vivo validation; single lab","pmids":["29978433"],"is_preprint":false},{"year":2006,"finding":"A biallelic frameshift mutation in BAF57/SMARCE1 exon 5 in BT549 breast cancer cells produces a truncated protein that has lost the ability to bind ERα but retains binding to nuclear receptor coactivator SRC1e. Expression of this truncated BAF57 increases SRC1e coactivation of ERα, suggesting gain-of-function oncogenic properties.","method":"Genomic DNA/cDNA sequencing, co-immunoprecipitation (ER binding and SRC1e binding), reporter assays","journal":"Breast cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for binding domain mapping, functional reporter assay, single lab","pmids":["16538531"],"is_preprint":false},{"year":2002,"finding":"Xenopus BAF57 (XBaf57) was isolated via expression cloning as a modulator of XSmad7. XBaf57 cooperates with XSmad7 to increase expression of neural markers in ectodermal explants, suggesting a role in neural induction.","method":"Expression cloning, ectodermal explant assay, in situ hybridization","journal":"Mechanisms of development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression assay in explants; no mechanistic pathway placement beyond cooperation with Smad7; single lab","pmids":["12128220"],"is_preprint":false}],"current_model":"SMARCE1/BAF57 is an integral subunit of all mammalian BAF (SWI/SNF) chromatin-remodeling complexes that performs multiple distinct functions: it structurally stabilizes the cBAF complex core-ATPase module interaction (loss of SMARCE1 shifts the balance toward ncBAF/BRD9 complexes and reduces chromatin accessibility at enhancers); it serves as a direct adapter between the SWI/SNF complex and nuclear hormone receptors (AR and ERα), binding the AR hinge/DBD region and the ERα hinge to enable ligand-activated transcription; it is required for proper SWI/SNF subunit stoichiometry (including BAF180 retention) and is itself regulated by proteasomal degradation controlled by BAF155/BAF170 levels; it forms SWI/SNF-independent complexes (e.g., with ILF3) to drive invasion; it regulates cell cycle progression through G2-M and transcription of cell-cycle genes; and germline loss-of-function mutations cause familial clear cell meningioma through a tumor-suppressor two-hit mechanism, while somatic mutations in its HMG or coiled-coil domains can produce gain-of-function oncogenic effects in breast cancer."},"narrative":{"mechanistic_narrative":"SMARCE1 (BAF57) is an integral subunit of mammalian SWI/SNF (BAF) chromatin-remodeling complexes that stabilizes complex architecture and couples remodeling activity to specific transcriptional programs [PMID:35681054, PMID:38357971]. It performs a structural role by stabilizing the canonical BAF core-ATPase interaction; its loss destabilizes cBAF on chromatin, reduces enhancer accessibility, and shifts the balance toward BRD9-containing ncBAF complexes, sensitizing cells to ncBAF inhibition [PMID:35681054]. SMARCE1 is required for proper subunit stoichiometry — its depletion co-depletes BAF180 from the complex — and is itself regulated by proteasomal degradation governed by the levels of its direct partners BAF155 (SMARCC1) and BAF170, with the SMARCE1–SMARCC1 interface mapped structurally and biochemically [PMID:16199878, PMID:20460533, PMID:35158202, PMID:29978433]. Through its HMG domain, which binds four-way-junction DNA, and through direct contacts with sequence-specific factors, SMARCE1 serves as an adapter that recruits SWI/SNF to defined loci, including direct binding of the androgen receptor DNA-binding/hinge region and the ERα hinge to enable ligand-activated transcription [PMID:15743818, PMID:18559499, PMID:16769725, PMID:33010889]. It governs cell-cycle progression and transcription of cell-cycle and developmental genes [PMID:20460533], and additionally acts within SWI/SNF-independent complexes — for example with ILF3 to drive basement-membrane invasion and with HIF1A to suppress anoikis — implicating it in cancer cell migration and metastasis [PMID:28377514, PMID:27495308]. Germline heterozygous loss-of-function mutations in SMARCE1 cause familial multiple spinal clear-cell meningiomas through a tumor-suppressor two-hit mechanism with loss of protein in tumors [PMID:23377182], whereas somatic truncation in breast cancer can yield gain-of-function effects, such as a truncated protein that loses ERα binding but retains and potentiates SRC1e coactivation [PMID:16538531].","teleology":[{"year":2002,"claim":"Established an early developmental role for BAF57 by showing it cooperates with a signaling effector to promote a tissue fate, hinting at chromatin remodeling in patterning before its complex role was defined.","evidence":"Expression cloning and ectodermal explant assays in Xenopus identifying XBaf57 as an XSmad7 modulator","pmids":["12128220"],"confidence":"Low","gaps":["Single overexpression explant assay without mechanistic placement","No demonstration of endogenous requirement","Mammalian relevance not addressed"]},{"year":2005,"claim":"Defined SMARCE1 as a direct adapter linking SWI/SNF to nuclear hormone receptor signaling, answering how a remodeler is targeted to hormone-responsive genes.","evidence":"Co-IP, ChIP on endogenous AR targets, siRNA knockdown and proliferation assays in prostate cancer cells","pmids":["15743818"],"confidence":"High","gaps":["Precise AR contact surface not yet mapped","Generality across other receptors untested at this stage"]},{"year":2005,"claim":"Showed BAF57 abundance is set by its core partners and proteasomal turnover, establishing how complex stoichiometry is enforced post-translationally.","evidence":"Exogenous expression, proteasome inhibition, Co-IP and deletion mapping of BAF57–BAF155 interaction","pmids":["16199878"],"confidence":"High","gaps":["Responsible E3 ligase not identified","Whether degradation regulates complex assembly dynamically unaddressed"]},{"year":2005,"claim":"Demonstrated tumor-suppressor activity by restoring BAF57 in deficient breast cells and identifying a direct pro-apoptotic transcriptional target.","evidence":"Stable re-expression, growth/apoptosis assays, microarray, ChIP and siRNA epistasis on CYLD","pmids":["16135788"],"confidence":"High","gaps":["Breadth of the BAF57 target gene program beyond CYLD unresolved","Mechanism of CYLD-dependent death not detailed"]},{"year":2006,"claim":"Extended the adapter model to ERα and defined receptor-subtype selectivity, mapping the ERα hinge as the recruitment determinant.","evidence":"siRNA knockdown, reporter assays and structure-function deletion mapping in breast cancer cells","pmids":["16769725"],"confidence":"High","gaps":["Structural basis of hinge recognition not resolved","Why ERβ is not engaged unexplained"]},{"year":2006,"claim":"Revealed a potential gain-of-function route in cancer: a truncating mutation that uncouples ERα binding from coactivator engagement.","evidence":"Sequencing of BT549 mutation, Co-IP for ER and SRC1e binding, reporter assays","pmids":["16538531"],"confidence":"Medium","gaps":["In vivo oncogenic consequence not established","Single cell line context"]},{"year":2007,"claim":"Identified a direct DNA-binding, gene-repressive activity by showing SMARCE1 binds and represses a viral promoter.","evidence":"EMSA, DNA-protein array and overexpression replication assay on HBV core promoter","pmids":["17669635"],"confidence":"Medium","gaps":["Whether repression requires the SWI/SNF complex unclear","Single lab functional validation"]},{"year":2008,"claim":"Mapped the AR recruitment domain and showed it is pharmacologically actionable, demonstrating a BAF57-derived peptide blocks AR chromatin residence.","evidence":"ChIP recruitment mapping and BIPep functional blockade in AR-positive prostate cancer cells","pmids":["18559499"],"confidence":"High","gaps":["Structural detail of the BAF57–AR interface not resolved","Specificity of peptide for AR vs other receptors not tested"]},{"year":2009,"claim":"Showed tissue-specific isoform diversity by characterizing neuron-enriched N-terminally truncated BAF57 isoforms that still assemble into SWI/SNF.","evidence":"RT-PCR, fractionation, Co-IP with Brg1/Brm/BAF155/BAF170 and overexpression effects on NRSE genes","pmids":["19245665"],"confidence":"Medium","gaps":["Endogenous functional role of isoforms in neurons untested","Single lab"]},{"year":2010,"claim":"Established SMARCE1 as required for SWI/SNF subunit composition and cell-cycle progression, linking complex integrity to G2-M control.","evidence":"SILAC quantitative proteomics of purified SWI/SNF, shRNA knockdown, cell cycle and colony formation assays","pmids":["20460533"],"confidence":"High","gaps":["Direct cell-cycle gene targets not fully enumerated","Mechanism of selective BAF180 co-depletion unclear"]},{"year":2013,"claim":"Defined disease causation: germline loss-of-function establishes SMARCE1 as a tumor suppressor for familial clear-cell meningioma via a two-hit mechanism.","evidence":"Exome and Sanger sequencing in families plus IHC for protein loss in tumors","pmids":["23377182"],"confidence":"High","gaps":["Molecular driver linking SMARCE1 loss to clear-cell histology not yet defined here","Second-hit events not enumerated"]},{"year":2013,"claim":"Showed elevated SMARCE1 can be pro-oncogenic, redirecting SWI/SNF occupancy to drive integrin-dependent prostate cancer migration.","evidence":"Expression analysis, ChIP at α2 integrin locus, migration assays and antibody blockade","pmids":["23493350"],"confidence":"Medium","gaps":["Single lab study","Mechanism of altered SWI/SNF locus targeting unresolved"]},{"year":2015,"claim":"Connected SMARCE1 loss to therapy resistance by showing it represses EGFR transcription via CBX2 regulation.","evidence":"ChIP at EGFR locus, siRNA knockdown, drug-resistance and rescue assays in NSCLC","pmids":["25656847"],"confidence":"High","gaps":["Direct vs CBX2-mediated repression contributions not separated","Generality across other RTKs untested"]},{"year":2016,"claim":"Identified a SWI/SNF-independent anoikis-protective axis through SMARCE1 potentiation of HIF1A and downstream FAK/ERK/AKT signaling.","evidence":"Co-IP, ChIP, siRNA epistasis with HIF1A and PTK2, xenograft lung metastasis model","pmids":["27495308"],"confidence":"High","gaps":["Whether the HIF1A interaction is fully SWI/SNF-independent not exhaustively shown","Direct target genes mediating survival not detailed"]},{"year":2017,"claim":"Demonstrated a SWI/SNF-independent invasion mechanism via a SMARCE1–ILF3 complex driving protease expression and metastasis.","evidence":"Knockdown, primary mammary tissue invasion assay, Co-IP and in vivo xenograft metastasis","pmids":["28377514"],"confidence":"High","gaps":["Structural basis of the ILF3 interaction unknown","Which proteases are direct transcriptional targets not fully resolved"]},{"year":2018,"claim":"Defined an in vivo developmental requirement, showing Smarce1 directs BAF recruitment to gata5 regulatory regions during cardiac/endocardial development.","evidence":"CRISPR knockout zebrafish, expression analysis and ChIP at gata5 locus","pmids":["30337622"],"confidence":"High","gaps":["Direct target gene network beyond gata5 not mapped","Conservation to mammalian heart development not tested here"]},{"year":2018,"claim":"Showed a peptide disrupting the BAF155–BAF57 interface destabilizes both subunits and is immunomodulatory in vivo, reinforcing the stoichiometric dependency.","evidence":"Nucleus-transducible ntBAF57-ΔPH fragment, Co-IP, T cell assays and in vivo sepsis model","pmids":["29978433"],"confidence":"Medium","gaps":["Mechanism of T cell suppression downstream of complex destabilization unclear","Single lab"]},{"year":2020,"claim":"Solved the HMG domain structure and quantified its four-way-junction DNA binding, providing a structural basis for SMARCE1's intrinsic DNA-recognition activity.","evidence":"X-ray crystallography at 2.55 Å and fluorescence quenching binding assay","pmids":["33010889"],"confidence":"High","gaps":["Role of 4WJ binding in vivo not established","Full-length protein structure unresolved"]},{"year":2020,"claim":"Implicated SMARCE1 in neuronal apoptosis by showing it is required for FoxO3a-driven PUMA induction in a Parkinson's disease model.","evidence":"siRNA knockdown, qPCR/Western, primary neurons and PC12 cells, in vivo 6-OHDA rat model","pmids":["31971251"],"confidence":"Medium","gaps":["Whether SMARCE1 acts through SWI/SNF at the PUMA locus not shown","Single lab"]},{"year":2021,"claim":"Linked SMARCE1 to stress-responsive alternative splicing through interaction with SRSF1 and control of cyclin D1 isoform choice.","evidence":"Co-IP with SRSF1, RT-PCR, knockdown/overexpression under mechanical stretch","pmids":["33670012"],"confidence":"Low","gaps":["Single Co-IP without reciprocal/structural validation","Direct role in splice-site selection mechanism untested"]},{"year":2022,"claim":"Provided the mechanistic explanation for clear-cell meningioma: SMARCE1 selectively stabilizes cBAF, and its loss rebalances toward ncBAF, creating a targetable dependency.","evidence":"Biochemical fractionation, ATAC-seq, genetic loss-of-function and ncBAF small-molecule inhibition in CCM cells and tumors","pmids":["35681054"],"confidence":"High","gaps":["Direct molecular contact stabilizing the core-ATPase module not structurally resolved","Why CCM tissue is uniquely sensitive not fully explained"]},{"year":2022,"claim":"Defined a feed-forward oncogenic loop in neuroblastoma where SMARCE1 enables MYCN target activation and MYCN drives SMARCE1 transcription.","evidence":"Co-IP, ChIP at MYCN targets and the SMARCE1 promoter, knockdown and rescue, reporter assays","pmids":["35978151"],"confidence":"Medium","gaps":["Structural basis of the SMARCE1–MYCN interaction unknown","Single lab study"]},{"year":2022,"claim":"Mapped the core-assembly interface biochemically, localizing the SMARCE1 region that engages SMARCC1 and reconstituting tetrameric core subcomplexes.","evidence":"Co-expression/co-purification, pulldown fragment mapping and crystallization (3.2 Å) of the SMARCC1/SMARCE1 binary complex","pmids":["35158202"],"confidence":"Medium","gaps":["Limited resolution and functional validation","How the interface controls in-cell complex integrity not shown"]},{"year":2024,"claim":"Established that Smarce1 is required for nucleosome stability and complex integrity, linking its loss to impaired heterochromatin formation during differentiation.","evidence":"Homozygous mutant mouse ESCs, sucrose gradient sedimentation, histone-binding and differentiation assays","pmids":["38357971"],"confidence":"High","gaps":["Molecular basis of altered nucleosome stability unresolved","Which differentiation genes are directly affected not enumerated"]},{"year":2025,"claim":"Identified Smarce1 as a cell-autonomous negative regulator of cardiomyocyte proliferation during heart development using converging genetic approaches.","evidence":"ENU mutant, morpholino, mRNA rescue and myocardium-specific overexpression with EdU proliferation readout in zebrafish","pmids":["40950410"],"confidence":"High","gaps":["Direct transcriptional targets controlling proliferation not yet defined here","Mammalian relevance untested"]},{"year":2026,"claim":"Resolved the downstream effector of cardiomyocyte proliferation control by defining a Smarce1–Stat3 axis acting through chromatin accessibility and cell-cycle dynamics.","evidence":"RNA-seq, scRNA-seq, ATAC-seq with genetic loss-of-function and pharmacological Stat3 modulation in zebrafish","pmids":["41808150"],"confidence":"High","gaps":["Direct Smarce1 occupancy at Stat3 pathway loci not shown","Conservation in mammalian cardiac regeneration untested"]},{"year":null,"claim":"How SMARCE1 mechanistically achieves locus selectivity — switching between SWI/SNF-dependent stabilization and SWI/SNF-independent partnerships (ILF3, HIF1A, SRSF1) — and the structural basis of its sequence-specific factor contacts remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No full-length structure of SMARCE1 within an assembled BAF complex","Determinants choosing SWI/SNF-dependent vs -independent complexes unknown","Genome-wide direct target map integrating contexts lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[15,18,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,3,5,9,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,3,7,8]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,6,17]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,17]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,17]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,3,5,9,14]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[6,19,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[18,19,20,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,8]}],"complexes":["cBAF (canonical SWI/SNF)","ncBAF (BRD9-containing)","SMARCE1-ILF3 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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. 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). Required for the coactivation of estrogen responsive promoters by SWI/SNF complexes and the SRC/p160 family of histone acetyltransferases (HATs). Also specifically interacts with the CoREST corepressor resulting in repression of neuronal specific gene promoters in non-neuronal cells","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q969G3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SMARCE1","classification":"Common Essential","n_dependent_lines":893,"n_total_lines":1208,"dependency_fraction":0.7392384105960265},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000073584","cell_line_id":"CID001682","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"chromatin","grade":2}],"interactors":[{"gene":"ARID1A","stoichiometry":10.0},{"gene":"ARID1B","stoichiometry":10.0},{"gene":"PHF10","stoichiometry":10.0},{"gene":"SMARCA2","stoichiometry":10.0},{"gene":"SMARCA4","stoichiometry":10.0},{"gene":"SMARCB1","stoichiometry":10.0},{"gene":"SMARCC1","stoichiometry":10.0},{"gene":"SMARCC2","stoichiometry":10.0},{"gene":"SMARCD1","stoichiometry":10.0},{"gene":"SMARCD2","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001682","total_profiled":1310},"omim":[{"mim_id":"616938","title":"COFFIN-SIRIS SYNDROME 5; CSS5","url":"https://www.omim.org/entry/616938"},{"mim_id":"614609","title":"COFFIN-SIRIS SYNDROME 4; CSS4","url":"https://www.omim.org/entry/614609"},{"mim_id":"614608","title":"COFFIN-SIRIS SYNDROME 3; CSS3","url":"https://www.omim.org/entry/614608"},{"mim_id":"614607","title":"COFFIN-SIRIS SYNDROME 2; CSS2","url":"https://www.omim.org/entry/614607"},{"mim_id":"614119","title":"TEASHIRT ZINC FINGER HOMEOBOX 3; TSHZ3","url":"https://www.omim.org/entry/614119"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SMARCE1"},"hgnc":{"alias_symbol":["BAF57"],"prev_symbol":[]},"alphafold":{"accession":"Q969G3","domains":[{"cath_id":"1.10.30.10","chopping":"53-166","consensus_level":"medium","plddt":89.4585,"start":53,"end":166},{"cath_id":"1.20.5","chopping":"225-274","consensus_level":"high","plddt":94.959,"start":225,"end":274}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969G3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969G3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969G3-F1-predicted_aligned_error_v6.png","plddt_mean":69.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMARCE1","jax_strain_url":"https://www.jax.org/strain/search?query=SMARCE1"},"sequence":{"accession":"Q969G3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969G3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969G3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969G3"}},"corpus_meta":[{"pmid":"23377182","id":"PMC_23377182","title":"Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas.","date":"2013","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23377182","citation_count":201,"is_preprint":false},{"pmid":"25168959","id":"PMC_25168959","title":"Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.","date":"2014","source":"American journal of medical genetics. 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In SMARCE1-deficient clear cell meningioma cells, cBAF complexes fail to stabilize on chromatin, reducing enhancer accessibility, and residual core module components increase formation of BRD9-containing non-canonical BAF (ncBAF) complexes. This combined attenuation of cBAF and increased ncBAF activity generates the CCM-specific gene expression signature, and SMARCE1-deficient cells exhibit heightened sensitivity to small-molecule ncBAF inhibition.\",\n      \"method\": \"Biochemical fractionation, chromatin accessibility assays (ATAC-seq), small-molecule inhibition, genetic loss-of-function in CCM cell lines and patient tumors\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical fractionation, chromatin accessibility, genetic rescue, pharmacological inhibition) in a single rigorous study with direct functional validation\",\n      \"pmids\": [\"35681054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"BAF57/SMARCE1 directly binds to the androgen receptor (AR) and is recruited to endogenous AR target loci upon ligand activation. Loss of BAF57 severely compromises AR-dependent transactivation in prostatic adenocarcinoma cells, and this activity requires SWI/SNF ATPase function. Both BAF57 and BRM are required for AR-dependent proliferation of prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), siRNA knockdown, reporter assays, cell proliferation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP on endogenous targets, rescue experiments, replicated by subsequent studies\",\n      \"pmids\": [\"15743818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BAF57/SMARCE1 is recruited to the AR DNA-binding domain/hinge region concomitant with receptor activation. A BAF57-derived inhibitory peptide (BIPep) blocks AR residence on chromatin and AR-dependent gene activation, inhibiting androgen-dependent prostate cancer cell proliferation in AR-positive cells.\",\n      \"method\": \"ChIP, peptide inhibitor functional assays, cell proliferation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP mapping of recruitment domain, peptide-based functional blockade, multiple cell line validation\",\n      \"pmids\": [\"18559499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BAF57/SMARCE1 is required for ERα-mediated transcription and estrogen-stimulated proliferation in breast cancer cells. Structure-function analysis defined a region within the ERα hinge domain as essential for BAF57 recruitment. BAF57 is an ER subtype-selective modulator, specifically regulating ERα- but not ERβ-mediated transcription.\",\n      \"method\": \"siRNA knockdown, reporter assays, structure-function deletion analysis, cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (knockdown, mutagenesis/deletion mapping, proliferation assays), replicated across constructs\",\n      \"pmids\": [\"16769725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Exogenous expression of BAF57/SMARCE1 or certain deletion mutants triggers proteasome-dependent degradation of endogenous BAF57. The protein levels of BAF155 and BAF170 dictate the maximum cellular amount of BAF57 through direct protein-protein interactions; specific interacting domains between BAF57 and BAF155 were mapped.\",\n      \"method\": \"Exogenous expression, proteasome inhibitor experiments, co-immunoprecipitation, deletion mapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (domain mapping, proteasome inhibition, Co-IP) demonstrating the regulatory mechanism\",\n      \"pmids\": [\"16199878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Re-expression of BAF57/SMARCE1 in BT549 breast carcinoma cells (which lack endogenous BAF57) induces growth arrest, contact inhibition, and apoptosis. ChIP analysis identified CYLD (familial cylindromatosis tumor suppressor) as a direct transcriptional target of BAF57. siRNA suppression of CYLD inhibited BAF57-mediated cell death.\",\n      \"method\": \"Stable cell line re-expression, growth assays, microarray, ChIP, siRNA knockdown\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirming direct target, siRNA rescue epistasis, multiple phenotypic readouts\",\n      \"pmids\": [\"16135788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Depletion of BAF57 from the SWI/SNF complex causes significant co-depletion of BAF180 from the complex without reducing total cellular BAF180 levels, establishing BAF57 as required for maintaining proper SWI/SNF subunit composition. BAF57 knockdown causes G2-M accumulation, inhibition of colony formation, and transcriptional misregulation of cell cycle genes involved in late G2.\",\n      \"method\": \"SILAC-based quantitative proteomics of affinity-purified SWI/SNF, shRNA knockdown, cell cycle analysis, colony formation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — quantitative proteomics (SILAC) plus multiple functional assays confirming complex composition and cell cycle role\",\n      \"pmids\": [\"20460533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SMARCE1 drives invasion of ductal carcinoma in situ (DCIS) by regulating expression of secreted proteases that degrade basement membrane. SMARCE1 forms a SWI/SNF-independent complex with transcription factor ILF3 to promote invasion. SMARCE1 is also required for metastasis in vivo in xenograft models.\",\n      \"method\": \"siRNA/shRNA knockdown, primary human mammary tissue invasion assay, in vivo xenograft metastasis, co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifying novel ILF3 complex, in vivo metastasis model, primary tissue functional assay\",\n      \"pmids\": [\"28377514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SMARCE1 interacts with and potentiates the transcriptional activity of HIF1A in response to loss of attachment (anoikis conditions). This leads to rapid PTK2 (FAK) activation and downstream ERK/AKT pathway activation, suppressing pro-apoptotic BIM. Both HIF1A and PTK2 are required for SMARCE1-mediated protection against anoikis and lung metastasis in vivo.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, xenograft metastasis model, ERK/AKT signaling assays\",\n      \"journal\": \"Breast cancer research : BCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ChIP, in vivo xenograft, multiple epistasis experiments with HIF1A and PTK2\",\n      \"pmids\": [\"27495308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SMARCE1 binds to regulatory regions of the EGFR locus and suppresses EGFR transcription, in part through regulating expression of Polycomb Repressive Complex component CBX2. SMARCE1 loss induces EGFR expression and confers resistance to MET and ALK inhibitors in non-small cell lung cancers.\",\n      \"method\": \"ChIP, siRNA knockdown, drug resistance assays, gene expression analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP at EGFR locus, CBX2 mechanism, pharmacological validation with EGFR inhibitor rescue\",\n      \"pmids\": [\"25656847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Heterozygous germline loss-of-function mutations in SMARCE1 cause familial multiple spinal meningiomas. Tumors from affected individuals show loss of SMARCE1 protein expression, consistent with a tumor suppressor two-hit mechanism. All mutation-associated tumors were of clear-cell histological subtype.\",\n      \"method\": \"Exome sequencing, Sanger sequencing, immunohistochemistry for SMARCE1 protein loss\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — exome discovery replicated in additional cases, IHC confirmation of protein loss, consistent two-hit pattern\",\n      \"pmids\": [\"23377182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Aberrant elevated BAF57/SMARCE1 expression in prostate cancer circumvents androgen-mediated signaling, induces α2 integrin upregulation via altered SWI/SNF occupancy at the α2 integrin locus, and confers a pro-metastatic migratory advantage that is attenuated by anti-α2 integrin antibody blockade.\",\n      \"method\": \"Gene expression analysis, ChIP at α2 integrin locus, cell migration assays, antibody blockade, immunohistochemistry of human specimens\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and functional migration assay, single lab study\",\n      \"pmids\": [\"23493350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Neuron-specific alternative splicing of BAF57/SMARCE1 exons II, III, and IV produces N-terminally truncated isoforms (N-BAF57s) predominantly expressed in the nervous system. These isoforms associate with Brg1, Brm, BAF155, and BAF170 into functional SWI/SNF complexes, and their overexpression in non-neural cells affects expression of NRSE-containing genes.\",\n      \"method\": \"RT-PCR, biochemical fractionation, co-immunoprecipitation, transient overexpression\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and fractionation confirming complex assembly, functional gene expression effect, single lab\",\n      \"pmids\": [\"19245665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BAF57/SMARCE1 is upregulated in a Parkinson's disease model (6-OHDA) and is required for induction of the pro-apoptotic protein PUMA by FoxO3a in dopaminergic neurons. BAF57 is necessary for FoxO3a-mediated transcriptional activation of PUMA, linking SWI/SNF chromatin remodeling to neuronal apoptosis in this context.\",\n      \"method\": \"siRNA knockdown, qPCR, Western blot, primary neuronal cultures and PC12 cells, in vivo 6-OHDA rat model\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function with defined phenotypic readout (PUMA induction, neuronal death), in vitro and in vivo, single lab\",\n      \"pmids\": [\"31971251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMARCE1 directly interacts with MYCN and is required for MYCN-mediated transcriptional activation of downstream target genes (PLK1, ODC1, E2F2) in neuroblastoma cells. Conversely, MYCN directly regulates SMARCE1 transcription through binding to a non-canonical E-box in the SMARCE1 promoter, creating a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, overexpression rescue, promoter reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP at target loci, rescue experiments; single lab study\",\n      \"pmids\": [\"35978151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of the HMG domain of BAF57/SMARCE1 was solved at 2.55 Å resolution. The domain consists of three α-helices in an L-shaped form stabilized by a hydrophobic core. Fluorescence quenching assays showed that BAF57-HMG binds four-way junction (4WJ) DNA with an affinity of ~296 nM, and the 4WJ DNA-binding site was identified structurally.\",\n      \"method\": \"X-ray crystallography, fluorescence quenching binding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at 2.55 Å with biochemical binding validation; single lab but Tier 1 method\",\n      \"pmids\": [\"33010889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The assembly mechanism of BAF core subunits was investigated; SMARCE1 (residues 210-284) interacts with SMARCC1 (residues 862-966). Binary, ternary, and tetrameric complexes of SMARCC1/SMARCD1/SMARCB1/SMARCE1 were reconstituted, and crystals of the SMARCC1(883-966)/SMARCE1(210-284) binary complex were obtained with diffraction data to 3.2 Å.\",\n      \"method\": \"Co-expression and co-purification, crystallography (3.2 Å), pulldown mapping of interacting fragments\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystallographic data obtained but resolution and functional validation limited; single lab\",\n      \"pmids\": [\"35158202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Disruption of Smarce1 in mouse embryonic stem cells (ESCs) causes dissociation of other SWI/SNF complex components, decreased nucleosome stability (loosened histone-DNA binding), and ectopic genomic redistribution of the SWI/SNF complex as shown by sucrose gradient sedimentation. Unstable nucleosomes persist during differentiation, impairing heterochromatin formation required for normal ESC differentiation.\",\n      \"method\": \"Homozygous mutant ESC generation, sucrose gradient sedimentation, histone binding assays, differentiation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods (fractionation, nucleosome stability assay, complex integrity) plus functional differentiation phenotype; single lab\",\n      \"pmids\": [\"38357971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Loss of smarce1 in zebrafish causes defects in endocardial development from early stages, leading to a misshapen heart tube and increased expression of cardiac transcription factors. Smarce1 binds to cis-regulatory regions of the gata5 gene and is necessary for recruitment of the BAF complex to these regions.\",\n      \"method\": \"CRISPR/Cas9 knockout zebrafish, gene expression analysis, ChIP at gata5 locus\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR loss-of-function with defined developmental phenotype and ChIP demonstrating direct genomic occupancy; single lab\",\n      \"pmids\": [\"30337622\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of smarce1 function in zebrafish (ENU mutant and morpholino knockdown) causes ventricular cardiomyocyte hyperproliferation without hypertrophy, while myocardium-specific overexpression reduces CM proliferation. Exogenous smarce1 mRNA injection rescues the hyperproliferative phenotype, establishing smarce1 as a cell-autonomous negative regulator of CM proliferation during heart development.\",\n      \"method\": \"ENU mutagenesis screen, morpholino knockdown, mRNA rescue, Tet-On myocardium-specific overexpression, EdU labeling, immunofluorescence\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic approaches (mutant, morphant, rescue, overexpression) all converging on same phenotype with quantitative CM proliferation readout\",\n      \"pmids\": [\"40950410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Smarce1 deficiency in zebrafish enhances cardiomyocyte proliferative activity by modulating cell cycle dynamics and chromatin accessibility. Integrative transcriptomic and epigenomic analysis revealed that Smarce1 regulates Stat3 signaling components. Genetic and pharmacological modulation of Stat3 confirmed its functional contribution to Smarce1-dependent CM proliferation, establishing a Smarce1-Stat3 axis in cardiac growth.\",\n      \"method\": \"RNA-seq, single-cell RNA-seq, ATAC-seq, genetic Smarce1 loss-of-function, pharmacological Stat3 modulation\",\n      \"journal\": \"Biological research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics (RNA-seq, scRNA-seq, ATAC-seq) plus orthogonal genetic and pharmacological epistasis; single lab\",\n      \"pmids\": [\"41808150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SMARCE1 binds directly to an HBV core promoter containing naturally occurring deletions, as demonstrated by gel shift assay and DNA-protein array. SMARCE1 overexpression represses HBV replication, demonstrating a direct functional role as a host repressor of HBV.\",\n      \"method\": \"Gel shift assay (EMSA), DNA-protein array, overexpression functional assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — EMSA and DNA-protein array with functional validation; single lab\",\n      \"pmids\": [\"17669635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BAF57/SMARCE1 interacts with splicing factor SRSF1 (as shown by co-immunoprecipitation), and mechanical stress-induced alternative splicing of cyclin D1 (producing cyclin D1b isoform) is regulated by BAF57/SMARCE1 in osteoblast and keratinocyte cell lines.\",\n      \"method\": \"Co-immunoprecipitation, RT-PCR, overexpression and siRNA knockdown, cyclic stretch mechanical stimulation\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP plus knockdown/overexpression data; partial mechanistic follow-up; single lab\",\n      \"pmids\": [\"33670012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A nucleus-transducible BAF57 fragment lacking proline-rich and HMG domains (ntBAF57-ΔPH) disrupts the interaction between BAF155 and BAF57, leading to proteasomal degradation of endogenous BAF57 and BAF155, and suppresses T cell activation. In vivo administration enhanced survival in sepsis-induced mice.\",\n      \"method\": \"Protein transduction into CD4+ T cells, co-immunoprecipitation, gene expression analysis, in vivo sepsis model\",\n      \"journal\": \"International journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP confirming disrupted BAF155-BAF57 interaction, functional T cell and in vivo validation; single lab\",\n      \"pmids\": [\"29978433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A biallelic frameshift mutation in BAF57/SMARCE1 exon 5 in BT549 breast cancer cells produces a truncated protein that has lost the ability to bind ERα but retains binding to nuclear receptor coactivator SRC1e. Expression of this truncated BAF57 increases SRC1e coactivation of ERα, suggesting gain-of-function oncogenic properties.\",\n      \"method\": \"Genomic DNA/cDNA sequencing, co-immunoprecipitation (ER binding and SRC1e binding), reporter assays\",\n      \"journal\": \"Breast cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for binding domain mapping, functional reporter assay, single lab\",\n      \"pmids\": [\"16538531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Xenopus BAF57 (XBaf57) was isolated via expression cloning as a modulator of XSmad7. XBaf57 cooperates with XSmad7 to increase expression of neural markers in ectodermal explants, suggesting a role in neural induction.\",\n      \"method\": \"Expression cloning, ectodermal explant assay, in situ hybridization\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression assay in explants; no mechanistic pathway placement beyond cooperation with Smad7; single lab\",\n      \"pmids\": [\"12128220\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMARCE1/BAF57 is an integral subunit of all mammalian BAF (SWI/SNF) chromatin-remodeling complexes that performs multiple distinct functions: it structurally stabilizes the cBAF complex core-ATPase module interaction (loss of SMARCE1 shifts the balance toward ncBAF/BRD9 complexes and reduces chromatin accessibility at enhancers); it serves as a direct adapter between the SWI/SNF complex and nuclear hormone receptors (AR and ERα), binding the AR hinge/DBD region and the ERα hinge to enable ligand-activated transcription; it is required for proper SWI/SNF subunit stoichiometry (including BAF180 retention) and is itself regulated by proteasomal degradation controlled by BAF155/BAF170 levels; it forms SWI/SNF-independent complexes (e.g., with ILF3) to drive invasion; it regulates cell cycle progression through G2-M and transcription of cell-cycle genes; and germline loss-of-function mutations cause familial clear cell meningioma through a tumor-suppressor two-hit mechanism, while somatic mutations in its HMG or coiled-coil domains can produce gain-of-function oncogenic effects in breast cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SMARCE1 (BAF57) is an integral subunit of mammalian SWI/SNF (BAF) chromatin-remodeling complexes that stabilizes complex architecture and couples remodeling activity to specific transcriptional programs [#0, #17]. It performs a structural role by stabilizing the canonical BAF core-ATPase interaction; its loss destabilizes cBAF on chromatin, reduces enhancer accessibility, and shifts the balance toward BRD9-containing ncBAF complexes, sensitizing cells to ncBAF inhibition [#0]. SMARCE1 is required for proper subunit stoichiometry — its depletion co-depletes BAF180 from the complex — and is itself regulated by proteasomal degradation governed by the levels of its direct partners BAF155 (SMARCC1) and BAF170, with the SMARCE1\\u2013SMARCC1 interface mapped structurally and biochemically [#4, #6, #16, #23]. Through its HMG domain, which binds four-way-junction DNA, and through direct contacts with sequence-specific factors, SMARCE1 serves as an adapter that recruits SWI/SNF to defined loci, including direct binding of the androgen receptor DNA-binding/hinge region and the ER\\u03b1 hinge to enable ligand-activated transcription [#1, #2, #3, #15]. It governs cell-cycle progression and transcription of cell-cycle and developmental genes [#6], and additionally acts within SWI/SNF-independent complexes — for example with ILF3 to drive basement-membrane invasion and with HIF1A to suppress anoikis — implicating it in cancer cell migration and metastasis [#7, #8]. Germline heterozygous loss-of-function mutations in SMARCE1 cause familial multiple spinal clear-cell meningiomas through a tumor-suppressor two-hit mechanism with loss of protein in tumors [#10], whereas somatic truncation in breast cancer can yield gain-of-function effects, such as a truncated protein that loses ER\\u03b1 binding but retains and potentiates SRC1e coactivation [#24].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established an early developmental role for BAF57 by showing it cooperates with a signaling effector to promote a tissue fate, hinting at chromatin remodeling in patterning before its complex role was defined.\",\n      \"evidence\": \"Expression cloning and ectodermal explant assays in Xenopus identifying XBaf57 as an XSmad7 modulator\",\n      \"pmids\": [\"12128220\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single overexpression explant assay without mechanistic placement\", \"No demonstration of endogenous requirement\", \"Mammalian relevance not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined SMARCE1 as a direct adapter linking SWI/SNF to nuclear hormone receptor signaling, answering how a remodeler is targeted to hormone-responsive genes.\",\n      \"evidence\": \"Co-IP, ChIP on endogenous AR targets, siRNA knockdown and proliferation assays in prostate cancer cells\",\n      \"pmids\": [\"15743818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise AR contact surface not yet mapped\", \"Generality across other receptors untested at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed BAF57 abundance is set by its core partners and proteasomal turnover, establishing how complex stoichiometry is enforced post-translationally.\",\n      \"evidence\": \"Exogenous expression, proteasome inhibition, Co-IP and deletion mapping of BAF57\\u2013BAF155 interaction\",\n      \"pmids\": [\"16199878\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Responsible E3 ligase not identified\", \"Whether degradation regulates complex assembly dynamically unaddressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated tumor-suppressor activity by restoring BAF57 in deficient breast cells and identifying a direct pro-apoptotic transcriptional target.\",\n      \"evidence\": \"Stable re-expression, growth/apoptosis assays, microarray, ChIP and siRNA epistasis on CYLD\",\n      \"pmids\": [\"16135788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of the BAF57 target gene program beyond CYLD unresolved\", \"Mechanism of CYLD-dependent death not detailed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended the adapter model to ERα and defined receptor-subtype selectivity, mapping the ERα hinge as the recruitment determinant.\",\n      \"evidence\": \"siRNA knockdown, reporter assays and structure-function deletion mapping in breast cancer cells\",\n      \"pmids\": [\"16769725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of hinge recognition not resolved\", \"Why ERβ is not engaged unexplained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a potential gain-of-function route in cancer: a truncating mutation that uncouples ERα binding from coactivator engagement.\",\n      \"evidence\": \"Sequencing of BT549 mutation, Co-IP for ER and SRC1e binding, reporter assays\",\n      \"pmids\": [\"16538531\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo oncogenic consequence not established\", \"Single cell line context\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified a direct DNA-binding, gene-repressive activity by showing SMARCE1 binds and represses a viral promoter.\",\n      \"evidence\": \"EMSA, DNA-protein array and overexpression replication assay on HBV core promoter\",\n      \"pmids\": [\"17669635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether repression requires the SWI/SNF complex unclear\", \"Single lab functional validation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the AR recruitment domain and showed it is pharmacologically actionable, demonstrating a BAF57-derived peptide blocks AR chromatin residence.\",\n      \"evidence\": \"ChIP recruitment mapping and BIPep functional blockade in AR-positive prostate cancer cells\",\n      \"pmids\": [\"18559499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the BAF57\\u2013AR interface not resolved\", \"Specificity of peptide for AR vs other receptors not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed tissue-specific isoform diversity by characterizing neuron-enriched N-terminally truncated BAF57 isoforms that still assemble into SWI/SNF.\",\n      \"evidence\": \"RT-PCR, fractionation, Co-IP with Brg1/Brm/BAF155/BAF170 and overexpression effects on NRSE genes\",\n      \"pmids\": [\"19245665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous functional role of isoforms in neurons untested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established SMARCE1 as required for SWI/SNF subunit composition and cell-cycle progression, linking complex integrity to G2-M control.\",\n      \"evidence\": \"SILAC quantitative proteomics of purified SWI/SNF, shRNA knockdown, cell cycle and colony formation assays\",\n      \"pmids\": [\"20460533\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cell-cycle gene targets not fully enumerated\", \"Mechanism of selective BAF180 co-depletion unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined disease causation: germline loss-of-function establishes SMARCE1 as a tumor suppressor for familial clear-cell meningioma via a two-hit mechanism.\",\n      \"evidence\": \"Exome and Sanger sequencing in families plus IHC for protein loss in tumors\",\n      \"pmids\": [\"23377182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular driver linking SMARCE1 loss to clear-cell histology not yet defined here\", \"Second-hit events not enumerated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed elevated SMARCE1 can be pro-oncogenic, redirecting SWI/SNF occupancy to drive integrin-dependent prostate cancer migration.\",\n      \"evidence\": \"Expression analysis, ChIP at α2 integrin locus, migration assays and antibody blockade\",\n      \"pmids\": [\"23493350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"Mechanism of altered SWI/SNF locus targeting unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected SMARCE1 loss to therapy resistance by showing it represses EGFR transcription via CBX2 regulation.\",\n      \"evidence\": \"ChIP at EGFR locus, siRNA knockdown, drug-resistance and rescue assays in NSCLC\",\n      \"pmids\": [\"25656847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs CBX2-mediated repression contributions not separated\", \"Generality across other RTKs untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a SWI/SNF-independent anoikis-protective axis through SMARCE1 potentiation of HIF1A and downstream FAK/ERK/AKT signaling.\",\n      \"evidence\": \"Co-IP, ChIP, siRNA epistasis with HIF1A and PTK2, xenograft lung metastasis model\",\n      \"pmids\": [\"27495308\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the HIF1A interaction is fully SWI/SNF-independent not exhaustively shown\", \"Direct target genes mediating survival not detailed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a SWI/SNF-independent invasion mechanism via a SMARCE1–ILF3 complex driving protease expression and metastasis.\",\n      \"evidence\": \"Knockdown, primary mammary tissue invasion assay, Co-IP and in vivo xenograft metastasis\",\n      \"pmids\": [\"28377514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ILF3 interaction unknown\", \"Which proteases are direct transcriptional targets not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined an in vivo developmental requirement, showing Smarce1 directs BAF recruitment to gata5 regulatory regions during cardiac/endocardial development.\",\n      \"evidence\": \"CRISPR knockout zebrafish, expression analysis and ChIP at gata5 locus\",\n      \"pmids\": [\"30337622\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target gene network beyond gata5 not mapped\", \"Conservation to mammalian heart development not tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed a peptide disrupting the BAF155–BAF57 interface destabilizes both subunits and is immunomodulatory in vivo, reinforcing the stoichiometric dependency.\",\n      \"evidence\": \"Nucleus-transducible ntBAF57-ΔPH fragment, Co-IP, T cell assays and in vivo sepsis model\",\n      \"pmids\": [\"29978433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of T cell suppression downstream of complex destabilization unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Solved the HMG domain structure and quantified its four-way-junction DNA binding, providing a structural basis for SMARCE1's intrinsic DNA-recognition activity.\",\n      \"evidence\": \"X-ray crystallography at 2.55 Å and fluorescence quenching binding assay\",\n      \"pmids\": [\"33010889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of 4WJ binding in vivo not established\", \"Full-length protein structure unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Implicated SMARCE1 in neuronal apoptosis by showing it is required for FoxO3a-driven PUMA induction in a Parkinson's disease model.\",\n      \"evidence\": \"siRNA knockdown, qPCR/Western, primary neurons and PC12 cells, in vivo 6-OHDA rat model\",\n      \"pmids\": [\"31971251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SMARCE1 acts through SWI/SNF at the PUMA locus not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked SMARCE1 to stress-responsive alternative splicing through interaction with SRSF1 and control of cyclin D1 isoform choice.\",\n      \"evidence\": \"Co-IP with SRSF1, RT-PCR, knockdown/overexpression under mechanical stretch\",\n      \"pmids\": [\"33670012\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal/structural validation\", \"Direct role in splice-site selection mechanism untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided the mechanistic explanation for clear-cell meningioma: SMARCE1 selectively stabilizes cBAF, and its loss rebalances toward ncBAF, creating a targetable dependency.\",\n      \"evidence\": \"Biochemical fractionation, ATAC-seq, genetic loss-of-function and ncBAF small-molecule inhibition in CCM cells and tumors\",\n      \"pmids\": [\"35681054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular contact stabilizing the core-ATPase module not structurally resolved\", \"Why CCM tissue is uniquely sensitive not fully explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a feed-forward oncogenic loop in neuroblastoma where SMARCE1 enables MYCN target activation and MYCN drives SMARCE1 transcription.\",\n      \"evidence\": \"Co-IP, ChIP at MYCN targets and the SMARCE1 promoter, knockdown and rescue, reporter assays\",\n      \"pmids\": [\"35978151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the SMARCE1–MYCN interaction unknown\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the core-assembly interface biochemically, localizing the SMARCE1 region that engages SMARCC1 and reconstituting tetrameric core subcomplexes.\",\n      \"evidence\": \"Co-expression/co-purification, pulldown fragment mapping and crystallization (3.2 Å) of the SMARCC1/SMARCE1 binary complex\",\n      \"pmids\": [\"35158202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited resolution and functional validation\", \"How the interface controls in-cell complex integrity not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that Smarce1 is required for nucleosome stability and complex integrity, linking its loss to impaired heterochromatin formation during differentiation.\",\n      \"evidence\": \"Homozygous mutant mouse ESCs, sucrose gradient sedimentation, histone-binding and differentiation assays\",\n      \"pmids\": [\"38357971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of altered nucleosome stability unresolved\", \"Which differentiation genes are directly affected not enumerated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified Smarce1 as a cell-autonomous negative regulator of cardiomyocyte proliferation during heart development using converging genetic approaches.\",\n      \"evidence\": \"ENU mutant, morpholino, mRNA rescue and myocardium-specific overexpression with EdU proliferation readout in zebrafish\",\n      \"pmids\": [\"40950410\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets controlling proliferation not yet defined here\", \"Mammalian relevance untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Resolved the downstream effector of cardiomyocyte proliferation control by defining a Smarce1–Stat3 axis acting through chromatin accessibility and cell-cycle dynamics.\",\n      \"evidence\": \"RNA-seq, scRNA-seq, ATAC-seq with genetic loss-of-function and pharmacological Stat3 modulation in zebrafish\",\n      \"pmids\": [\"41808150\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Smarce1 occupancy at Stat3 pathway loci not shown\", \"Conservation in mammalian cardiac regeneration untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SMARCE1 mechanistically achieves locus selectivity — switching between SWI/SNF-dependent stabilization and SWI/SNF-independent partnerships (ILF3, HIF1A, SRSF1) — and the structural basis of its sequence-specific factor contacts remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No full-length structure of SMARCE1 within an assembled BAF complex\", \"Determinants choosing SWI/SNF-dependent vs -independent complexes unknown\", \"Genome-wide direct target map integrating contexts lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [15, 18, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 3, 5, 9, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 3, 7, 8]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 6, 17]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 17]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 3, 5, 9, 14]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [6, 19, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [18, 19, 20, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 8]}\n    ],\n    \"complexes\": [\"cBAF (canonical SWI/SNF)\", \"ncBAF (BRD9-containing)\", \"SMARCE1-ILF3 complex\"],\n    \"partners\": [\"SMARCC1\", \"SMARCC2\", \"AR\", \"ESR1\", \"ILF3\", \"HIF1A\", \"MYCN\", \"SRSF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}