Affinage

SMARCA4

SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4 · UniProt P51532

Round 2 corrected
Length
1647 aa
Mass
184.6 kDa
Annotated
2026-04-28
130 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMARCA4 (BRG1) is the catalytic ATPase subunit of mammalian SWI/SNF (BAF/PBAF) chromatin-remodeling complexes, coupling ATP hydrolysis to nucleosome displacement to regulate transcription, enhancer accessibility, DNA replication, and higher-order chromatin architecture. Together with a core of INI1, BAF155, and BAF170, BRG1 reconstitutes near-complete nucleosome remodeling activity, and combinatorial assembly of tissue-specific BAF subunits diversifies the complex for developmental and cell-type-specific gene programs including embryonic stem cell pluripotency and vascular endothelial identity (PMID:10078207, PMID:19279220, PMID:23406903). BRG1 is recruited to target loci through interactions with transcription factors (RB, BRCA1, STAT3, β-catenin/TERT, glucocorticoid receptor pioneer factors FOXA1/GATA3, SOX10) and its own bromodomain-AT-hook DNA-binding module, while its activity is post-translationally regulated by CK1δ/FBW7-mediated ubiquitin-proteasomal degradation, OTUD6A deubiquitination, CaMKII phosphorylation, and direct inhibition by lncRNAs Xist and Evf2 (PMID:7923370, PMID:29792595, PMID:30177679, PMID:35233061, PMID:34260936, PMID:30664740). Inactivating mutations cause dominant-negative loss of chromatin accessibility at active enhancers, aberrant H3K27me3 accumulation, replication stress with RPA-complex engagement, and metabolic rewiring toward glutamine/OXPHOS dependency, creating therapeutic vulnerabilities to ATR inhibition, KDM6 inhibition, and glutamine-transport competition (PMID:29323272, PMID:32690724, PMID:34262032, PMID:37210563).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Establishing BRG1 as a functional SWI2/SNF2 ATPase homolog answered whether mammals possess a catalytic chromatin-remodeling enzyme equivalent to yeast SWI2, and showed its ATPase activity is essential for transcriptional function.

    Evidence Yeast complementation with chimeric SWI2/BRG1, ATPase-dead K→R mutation abolishes activity in yeast and human cells

    PMID:8232556

    Open questions at the time
    • No mammalian complex partners yet identified
    • No nucleosome substrate assay performed
    • Mechanism of transcriptional activation unknown
  2. 1994 High

    Demonstrating that BRG1 physically and functionally cooperates with the retinoblastoma protein RB linked chromatin remodeling to cell cycle control, answering how SWI/SNF activity intersects with tumor suppression.

    Evidence Yeast two-hybrid and reciprocal co-IP showing RB pocket–BRG1 interaction; disruption by E1A or RB-binding motif mutation abolishes growth arrest in SW13 cells

    PMID:7923370

    Open questions at the time
    • Target genes of RB-BRG1 complex unidentified
    • In vivo relevance untested
  3. 1996 High

    Purification and functional characterization of the mammalian BAF complex established BRG1 as the ATPase engine of a multi-subunit nucleosome remodeling machine with cell-type-variable composition.

    Evidence Affinity purification of 9–12 subunit BAF complex; in vitro nucleosome disruption and transcription factor access assays; demonstration that BRG1 and BRM reside in separate complexes

    PMID:8804307 PMID:8895581

    Open questions at the time
    • Minimal functional core not yet defined
    • Structural basis of subunit assembly unknown
  4. 1999 High

    Reconstitution of the minimal functional core (BRG1 + INI1 + BAF155 + BAF170) resolved which subunits are necessary and sufficient for nucleosome remodeling activity.

    Evidence In vitro nucleosome remodeling with purified recombinant proteins

    PMID:10078207

    Open questions at the time
    • Role of accessory subunits (BAF60, BAF53, β-actin) in modulating activity not fully characterized
    • No structural model of assembled core
  5. 2000 High

    Identification of the RB–BRG1–HDAC repressor complex at cyclin E/A promoters and the BRCA1–BRG1 interaction established that BRG1 functions as both a transcriptional activator and repressor depending on its co-recruited partners.

    Evidence Co-IP and ChIP showing RB–BRG1–HDAC complex persists after CDK4 phosphorylation at cyclin A/CDC2 promoters; BRCA1 copurifies with BRG1 and requires it for p53-dependent transactivation

    PMID:10778858 PMID:10943845

    Open questions at the time
    • Genome-wide scope of repressive vs. activating BRG1 occupancy unknown
    • How BRCA1 directs BRG1 to specific loci unclear
  6. 2004 High

    BRG1 reintroduction into BRG1-deficient tumor cells demonstrated that BRG1 directly activates CDK inhibitor genes (p21, p15) and cooperates with STAT3 to open chromatin and enable transcriptional elongation, providing a mechanistic basis for its tumor-suppressive function.

    Evidence BRG1 rescue in ALAB breast cancer cells upregulates p21/p15 and suppresses E2F targets; STAT3 recruits BRG1 to p21 promoter enabling H3 acetylation and Pol II CTD-Ser2 phosphorylation

    PMID:14673169 PMID:15286705

    Open questions at the time
    • Relative contribution of BRG1's remodeling vs. scaffolding role at these loci not dissected
    • STAT3–BRG1 interaction based on single-lab co-IP
  7. 2009 High

    Discovery that TERT recruits BRG1 to β-catenin target gene promoters and that embryonic stem cells assemble a specialized esBAF complex revealed BRG1 as a central node linking Wnt signaling, telomerase biology, and pluripotency maintenance.

    Evidence TERT–BRG1 co-IP plus ChIP at Wnt target promoters in Xenopus and mouse; quantitative proteomics defining esBAF (BRG1-exclusive, BAF155-only) required for ES cell self-renewal

    PMID:19279220 PMID:19571879

    Open questions at the time
    • Whether TERT enzymatic activity is required for the BRG1 interaction unclear
    • How esBAF is disassembled during differentiation not established
  8. 2011 High

    Endothelial conditional knockout revealed BRG1 controls vascular Wnt signaling at two levels—Wnt receptor transcription and β-catenin target gene activation—and subsequently showed BRG1 specifies venous identity via COUP-TFII chromatin remodeling.

    Evidence Conditional Brg1 deletion in embryonic endothelium; pharmacological β-catenin rescue; ChIP at COUP-TFII regulatory elements

    PMID:21262838 PMID:23406903

    Open questions at the time
    • Upstream signals that activate BRG1 in endothelial cells unknown
    • Arterio-venous BRG1 regulatory mechanisms not dissected at single-cell level
  9. 2014 High

    Genome-wide ChIP-seq in embryonic tissues demonstrated that BRG1 predominantly occupies tissue-specific distal regulatory elements (enhancers) carrying both active (H3K27ac) and repressive (H3K27me3) marks, redefining BRG1 as a dual-function enhancer regulator.

    Evidence FLAG knock-in ChIP-seq across multiple embryonic tissues with histone mark co-mapping and transgenic enhancer validation

    PMID:24752179

    Open questions at the time
    • How BRG1 switches between activating and repressive states at the same locus not resolved
    • Whether all distal sites require ATPase activity unknown
  10. 2017 High

    Structural and functional dissection of the BRG1 bromodomain revealed multivalent DNA and H3K14ac binding, while cancer-associated ATPase mutations were shown to act as dominant negatives depleting chromatin accessibility at active enhancers genome-wide.

    Evidence NMR/ITC of bromodomain–DNA and bromodomain–H3K14ac interactions; ATAC-seq/ChIP-seq in cells expressing heterozygous dominant-negative ATPase-dead BRG1

    PMID:28706277 PMID:29323272

    Open questions at the time
    • Full-length BRG1 structural model absent
    • Whether dominant-negative effect operates through poison-subunit incorporation into all BAF subtypes untested
  11. 2018 High

    Identification of the CK1δ–FBW7 ubiquitin-dependent degradation pathway for BRG1, and the PTEN/AKT/GSK3β axis that stabilizes BRG1 in prostate cancer, established post-translational proteolysis as a major regulatory layer controlling BRG1 protein levels.

    Evidence In vitro kinase assay (CK1δ phosphorylates Ser31/35), ubiquitination assay, mutagenesis; PTEN-loss stabilizes BRG1 via AKT/GSK3β/FBXW7 inhibition in genetically engineered mice and organoids

    PMID:30177679 PMID:30496141

    Open questions at the time
    • Whether other E3 ligases target BRG1 unknown
    • Tissue-specific regulation of BRG1 turnover not mapped
  12. 2019 High

    Demonstration that lncRNAs Xist and Evf2 directly bind and inhibit BRG1 ATPase/remodeling activity introduced RNA-mediated regulation as a mechanism for silencing BRG1 at specific genomic loci, including the inactive X chromosome.

    Evidence In vitro ATPase and remodeling assays with purified BRG1 and RNA; Xist deletion restores BRG1 binding to Xi with consequent TAD/superloop formation; Evf2 converts active enhancers to repressed state in developing forebrain

    PMID:26138476 PMID:30664740

    Open questions at the time
    • RNA-binding domain of BRG1 not structurally resolved
    • Scope of regulatory lncRNAs beyond Xist and Evf2 unexplored
  13. 2020 High

    BRG1 loss was found to cause replication stress through deregulated CDC6-mediated origin firing, with BRG1-containing complexes physically engaging RPA, revealing a non-transcriptional role in replication fork stability.

    Evidence Single-molecule DNA fiber analysis, quantitative MS interactome, co-IP of BRG1–RPA; selective ATR inhibitor sensitivity of BRG1-deficient lung cancer

    PMID:32690724

    Open questions at the time
    • Direct mechanistic link between chromatin remodeling and origin licensing not established
    • Whether the RPA interaction is BAF- or PBAF-specific unknown
  14. 2021 High

    CaMKII-dependent phosphorylation of BRG1 in neurons was shown to alter its interactions with NuRD and cohesin, governing activity-dependent enhancer activation and behavior, revealing a signaling-responsive switch for BRG1 function.

    Evidence Phospho-site knockin mice; co-IP showing phosphorylation-dependent NuRD/cohesin interaction changes; ChIP-seq and RNA-seq; anxiety-like behavioral phenotype

    PMID:34260936

    Open questions at the time
    • Kinase(s) responsible for basal BRG1 phosphorylation at other sites not identified
    • Whether phosphorylation alters BAF complex composition in neurons untested
  15. 2022 High

    OTUD6A was identified as a deubiquitinase that stabilizes BRG1 by removing K27-linked polyubiquitin chains, complementing the FBW7-mediated degradation axis and revealing bidirectional ubiquitin regulation of BRG1 levels.

    Evidence MS screen, co-IP, in vitro and cellular ubiquitination assays, xenograft/PDX validation

    PMID:35233061

    Open questions at the time
    • Whether OTUD6A targets BRG1 in all tissues or is context-specific unknown
    • Interplay between K27-linked and K48-linked ubiquitination on BRG1 uncharacterized
  16. 2023 High

    SMARCA4 loss was shown to rewire cellular metabolism by repressing GLUT1, reducing glycolysis, and creating dependency on glutamine import via SLC38A2 for OXPHOS, identifying a metabolic vulnerability exploitable by alanine competition.

    Evidence CRISPR KO, metabolic flux assays, glucose uptake measurements, RNA-seq, alanine supplementation in PDX models

    PMID:37210563

    Open questions at the time
    • Whether metabolic rewiring occurs in all SMARCA4-mutant cancer types unknown
    • Direct chromatin mechanism linking BRG1 to GLUT1 transcription not fully delineated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Outstanding questions include the high-resolution cryo-EM structure of full-length BRG1 within assembled BAF and PBAF complexes, the complete catalog of regulatory lncRNAs that modulate BRG1 activity, the mechanistic basis by which BRG1 switches between activating and repressive functions at the same enhancer, and whether the replication-fork-protective role of BRG1 operates through direct chromatin remodeling at origins or through an independent scaffolding function.
  • Full-length BRG1 cryo-EM structure in BAF/PBAF context not yet available
  • Systematic identification of regulatory RNAs targeting BRG1 not performed
  • Remodeling-independent scaffolding functions not formally dissected from ATPase-dependent roles

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 7 GO:0140657 ATP-dependent activity 6 GO:0003723 RNA binding 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 4 GO:0005654 nucleoplasm 2 GO:0005694 chromosome 2
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-4839726 Chromatin organization 5 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-69306 DNA Replication 1
Partners
ARID1ABRCA1CTNNB1RB1SMARCB1SMARCC1SMARCC2TERT
Complex memberships
BAF (SWI/SNF-A)PBAF (SWI/SNF-B)esBAF

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 BRG1 encodes a 205 kDa nuclear protein containing a DNA-dependent ATPase domain homologous to SWI2/SNF2; a SWI2/BRG1 chimera with the ATPase domain replaced by human sequence rescued mitotic growth and transcriptional activation in swi2- yeast, while point mutation of the conserved ATP-binding lysine abolished complementation and exerted a dominant-negative effect; the same lysine-to-arginine substitution in BRG1 generated a transcriptional dominant negative in human cells. Yeast complementation, site-directed mutagenesis, dominant-negative overexpression in human cells Nature High 8232556
1994 BRG1 physically interacts with the retinoblastoma protein (RB) via a conserved RB-binding motif; the interaction requires the hypophosphorylated form of RB and the A/B pocket; BRG1-RB cooperation is required for BRG1-induced growth arrest (flat cell formation) in SW13 carcinoma cells, and sequestration of RB by adenovirus E1A or mutation of the RB-binding motif in BRG1 abolishes this activity. Yeast two-hybrid, co-immunoprecipitation, dominant-negative BRG1 expression, functional rescue assay Cell High 7923370
1996 BRG1 was purified as part of a mammalian SWI/SNF complex of 9–12 proteins (BRG1-associated factors, BAFs); the BRG1 complex can disrupt nucleosomes and facilitate binding of GAL4-VP16 to nucleosomal templates in vitro; BRG1 and hBRM are present in separate, distinct complexes with heterogeneous subunit compositions across cell types. Affinity purification, microsequencing, in vitro nucleosome disruption assay, GAL4-VP16 chromatin binding assay The EMBO journal High 8895581
1996 The mammalian SWI/SNF complex exists in multiple forms with distinct subunit compositions; BAF60b is found in a complex that shares some but not all subunits with the BRG1 complex; tissue-specific BAF subunits (BAF60b in muscle, BAF60c in pancreas) diversify the complex for developmental functions. Affinity purification, cDNA cloning, co-immunoprecipitation Genes & development High 8804307
1998 Antigen receptor signaling induces rapid association of the BRG1-containing BAF complex with chromatin; phosphatidylinositol 4,5-bisphosphate (PIP2) is sufficient in vitro to target the BAF complex to chromatin but has no effect on related complexes containing SNF2L/hISWI; β-actin and BAF53 (actin-related protein) are subunits of the BAF complex required for maximal BRG1 ATPase activity and for chromatin/matrix association. Biochemical fractionation, in vitro chromatin-targeting assay with PIP2, peptide sequencing, ATPase assay Cell High 9845365
1999 Both BRG1 and hBRM, as purified proteins, are capable of remodeling mono-nucleosomes and nucleosomal arrays in an ATP-dependent manner; addition of INI1, BAF155, and BAF170 to BRG1 increases remodeling activity to levels comparable to the whole hSWI/SNF complex, defining the functional core. In vitro nucleosome remodeling reconstitution with purified recombinant subunits Molecular cell High 10078207
2000 RB forms a repressor complex containing HDAC and the hSWI/SNF (BRG1-containing) nucleosome remodeling complex that inhibits transcription of cyclins E and A; phosphorylation of RB by cyclin D/CDK4 disrupts the HDAC association but the Rb-hSWI/SNF complex persists and maintains repression of cyclin A and CDC2 genes, controlling exit from S phase. Co-immunoprecipitation, chromatin immunoprecipitation, reporter assays, dominant-negative BRG1 Cell High 10778858
2000 BRCA1 directly interacts with the BRG1 subunit of a SWI/SNF-related complex isolated from human cells; this complex displays chromatin-remodeling activity; p53-mediated transcriptional stimulation by BRCA1 is abrogated by dominant-negative BRG1 or by the cancer-causing BRCA1 exon 11 deletion. Affinity/conventional chromatography, mass spectrometry, direct binding assay, dominant-negative functional assay Cell High 10943845
2001 BRG1 fractionates into two biochemically distinct complexes (differing in activity and subunit composition), while hBRM forms one complex with lower remodeling activity; one BRG1 complex and the hBRM complex contain components of the mSin3 repressor complex; BRG1, hBRM, and BAF155 directly interact with mSin3A in vitro, linking hSWI/SNF complexes to gene repression. Epitope-tag affinity purification, nucleosome remodeling assay, restriction enzyme accessibility assay, ATPase assay, in vitro pulldown Genes & development High 11238380
2001 LKB1 (STK11) physically associates with BRG1 via LKB1's N-terminus and BRG1's helicase domain; LKB1 stimulates BRG1 ATPase activity; expression of kinase-dead LKB1 (SL26) blocks BRG1-dependent growth arrest (flat cell formation) in SW13 cells, indicating LKB1 is required for BRG1-mediated growth arrest. Co-immunoprecipitation, in vitro pulldown, ATPase assay, dominant-negative functional assay The Journal of biological chemistry High 11445556
2002 hELD/OSA1 (ARID1A homolog) is a BRG1-interacting protein; the EHD2 domain of hELD/OSA1 mediates direct binding to BRG1; hELD/OSA1 is present in endogenous SWI/SNF complexes from mouse brain. cDNA cloning, co-immunoprecipitation, in vitro binding domain mapping The Biochemical journal Medium 11988099
2004 BRG1 reintroduction into BRG1-mutant breast tumor cells (ALAB) induced growth arrest associated with up-regulation of CDK inhibitors p21 and p15 and down-regulation of E2F targets (cyclin E); p21 protein was recruited to a complex with CDK2 inhibiting its activity; BRG1 associates with the p21 promoter in a p53-independent manner. Cell line rescue (BRG1 reintroduction), chromatin immunoprecipitation, CDK2 kinase assay, co-immunoprecipitation, microarray/real-time PCR Molecular and cellular biology High 14673169
2004 STAT3 associates with BRG1 by co-immunoprecipitation and pulldown; STAT3 DNA binding recruits BRG1 to the p21waf1 promoter, resulting in histone H3 acetylation and increased chromatin accessibility; BRG1 loading is followed by RNA polymerase II association and subsequent CDK9-mediated Ser2 phosphorylation of the CTD, enabling transcription elongation. Co-immunoprecipitation, pulldown, chromatin immunoprecipitation, restriction enzyme accessibility (Southern blot) Oncogene Medium 15286705
2006 BRG1-mediated activation of the CSF1 gene results in Z-DNA formation at a TG repeat within the promoter; BRG1 disrupts a positioned nucleosome at the silent CSF1 promoter; both BRG1 activity and Z-DNA formation are required for effective chromatin remodeling, with Z-DNA promoting the transition from transient to extensive nucleosome disruption. Chromatin immunoprecipitation, nucleosome mapping, Z-DNA specific antibody staining, reporter assay Molecular and cellular biology Medium 16537901
2009 TERT (telomerase reverse transcriptase) interacts with BRG1 and activates Wnt-dependent reporters; TERT physically occupies promoters of Wnt-dependent genes in vivo; TERT-BRG1 interaction places BRG1 as a cofactor in a β-catenin transcriptional complex modulating the Wnt/β-catenin signaling pathway. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), luciferase reporter assay, Xenopus embryo knockdown, mouse knockout Nature High 19571879
2009 ES cells express a specialized esBAF complex defined by the presence of BRG1 (not BRM), BAF155 (not BAF170), and BAF60A (not BAF60C); this specific subunit composition is required for ES cell self-renewal and pluripotency; esBAF directly interacts with key pluripotency regulators. Quantitative proteomics, conditional knockout in ES cells, co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 19279220
2011 BRG1 deletion from embryonic blood vessel endothelium results in down-regulation of Frizzled Wnt receptors, degradation of β-catenin, and decreased Wnt signaling; pharmacological β-catenin stabilization substantially rescues BRG1 mutant vascular phenotypes; BRG1 regulates canonical Wnt signaling at two levels — transcription of Wnt receptor genes and Wnt target genes. Conditional knockout mouse, pharmacological rescue, qRT-PCR, chromatin immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 21262838
2013 BRG1 promotes venous endothelial identity by binding conserved regulatory elements within the COUP-TFII promoter and remodeling chromatin to make it accessible to transcriptional machinery; conditional Brg1 deletion from vascular endothelium downregulates COUP-TFII and causes aberrant arterial marker expression on veins. Conditional knockout mouse, chromatin immunoprecipitation, chromatin accessibility assay Development (Cambridge, England) High 23406903
2014 SMARCA4/BRG1 binding in embryonic mouse tissues is predominantly distal from promoters and largely tissue-specific (73% of distal sites confined to one or few tissues); SMARCA4 associates with both active (H3K27ac) and repressive (H3K27me3) chromatin states at distal regulatory elements, indicating dual activating/repressive functions at enhancers in vivo. ChIP-seq with FLAG knock-in mouse, histone modification ChIP-seq, transgenic enhancer assays Genome research High 24752179
2015 BRG1 directly interacts with DLX1 and the lncRNA Evf2 through distinct binding sites; Evf2 directly inhibits BRG1 ATPase and chromatin remodeling activities in vitro; in the developing forebrain, Evf2 colocalizes with BRG1, increases BRG1 association with enhancers, yet converts active enhancers to repressed enhancers by inhibiting chromatin remodeling; mutations causing Coffin-Siris syndrome localize to the RNA-binding and DLX1-binding domains of BRG1. Mass spectrometry, co-immunoprecipitation, in vitro ATPase assay, in vitro chromatin remodeling assay, ChIP, live-cell imaging Development (Cambridge, England) High 26138476
2016 Zebrafish Brg1 is essential for adult heart regeneration; injury-induced Brg1 interacts with Dnmt3ab and suppresses expression of cdkn1c by increasing CpG methylation at its promoter, thereby repressing CDK inhibitor expression and enabling myocardial proliferation. Transgenic dominant-negative Brg1 overexpression, co-immunoprecipitation, bisulfite sequencing, RNA-seq, RNAscope Nature communications High 27929112
2016 SMARCA4/Brg1 coordinates Shh-type medulloblastoma transcriptional program by interacting with Gli1, Atoh1, and REST; Brg1 modulates the activity of H3K27me3 modifiers (Polycomb) to regulate medulloblastoma gene expression; Brg1 deletion inhibits tumor formation and progression in a mouse Shh-MB model. Conditional knockout mouse model, genome-wide expression profiling, ChIP, co-immunoprecipitation Oncogene High 27065321
2017 The BRG1 bromodomain (BRD) has moderate specificity for H3K14ac and unexpectedly also binds DNA through a basic patch surface; the BRD and adjacent AT-hook make multivalent contacts with DNA with moderate specificity for AT-rich elements; BRD can bind DNA and H3K14ac simultaneously, but DNA rather than histone binding drives nucleosome association in vitro, while neither contributes to global chromatin affinity of BRG1 in mouse ES cells. NMR, ITC, fluorescence polarization, in vitro nucleosome binding assay, ChIP-seq in mouse ES cells Nature communications High 28706277
2017 SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical remodeling cycle; heterozygous expression of these dominant-negative mutants alters open chromatin at thousands of genomic sites, specifically depleting accessibility at active enhancers (losing H3K27ac) predominantly in A compartments; this correlates with pro-oncogenic transcriptional changes including increased MYC expression. Biochemical ATPase assay, ATAC-seq, ChIP-seq, RNA-seq, dominant-negative mutant cell lines Nature structural & molecular biology High 29323272
2018 BRG1 is a ubiquitin substrate of SCF-FBW7; CK1δ phosphorylates BRG1 at Ser31/Ser35, facilitating FBW7 binding and subsequent ubiquitination-mediated degradation; stabilization of BRG1 in gastric cancer cells suppresses E-cadherin expression and promotes metastasis. Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, site-directed mutagenesis, cell migration/invasion assay Nature communications High 30177679
2018 BRG1 is required for proper glucocorticoid receptor (GR) transcriptional response in breast cancer cells; BRG1 pre-occupies GR binding sites prior to hormone exposure; BRG1 knockdown blocks recruitment of pioneer factors FOXA1 and GATA3 to GR binding sites, and GR interaction with FOXA1/GATA3 sites is restricted to BRG1 pre-bound loci. ChIP-seq, siRNA knockdown, hormone treatment, ATAC-seq eLife High 29792595
2018 Brg1 interacts with β-catenin to potentiate Wnt signaling in hepatocytes; Brg1 recruits lysine demethylase 4 (KDM4) to activate β-catenin target genes; hepatocyte-specific Brg1 deletion compromises liver regeneration and dampens survival after partial hepatectomy. Hepatocyte-specific conditional knockout, co-immunoprecipitation, ChIP, partial hepatectomy model FASEB journal Medium 30001167
2018 BRG1 binds to Sox9 promoter regulatory regions and is critical for SOX9 expression in acinar cells; BRG1 recruits upstream regulators PDX1 to the Sox9 promoter and enhancer; BRG1/SOX9 axis is required for acinar-to-ductal metaplasia and PanIN formation in Kras-driven pancreatic tumorigenesis. Conditional knockout mouse (Ptf1a-CreER; KrasG12D; Brg1fl/fl), ChIP, Sox9 rescue overexpression, organoid assay The Journal of clinical investigation High 30010625
2019 BRG1 loss in prostate cancer cells is synthetically lethal with PTEN loss; PTEN loss stabilizes BRG1 protein through inhibition of the AKT/GSK3β/FBXW7 degradation axis; increased BRG1 in PTEN-deficient cells drives a protumorigenic chromatin configuration causing BRG1 addiction. Genetically engineered mice, organoid assays, co-immunoprecipitation, western blotting, pharmacological BRG1 inhibitor The Journal of clinical investigation High 30496141
2019 Xist lncRNA directly interacts with BRG1 in vitro and in cell culture; RNA binding inhibits BRG1 nucleosome-remodeling and ATPase activities in vitro; Xist expels BRG1 from the inactive X chromosome (Xi), and Xist deletion leads to selective return of BRG1 to the Xi correlating with cohesin binding, TAD restoration, and de novo superloop formation. In vitro ATPase assay, in vitro remodeling assay, RNA immunoprecipitation, ATAC-seq, Hi-C/ChIP-seq Nature structural & molecular biology High 30664740
2019 BRG1 interacts with RORγ to be recruited to the Elovl3 promoter; BRG1 interacts with histone acetyltransferase p300 at the Elovl3 promoter to activate transcription; BRG1 knockdown attenuates prostate cancer cell migration and invasion concomitant with Elovl3 down-regulation. Co-immunoprecipitation, ChIP, siRNA knockdown, migration/invasion assay Biochimica et biophysica acta. Gene regulatory mechanisms Medium 31154107
2020 BRG1 deletion in lung cancer leads to replication stress with increased origin firing mediated by CDC6; BRG1-containing SWI/SNF complexes interact with RPA complexes as shown by quantitative mass spectrometry and co-immunoprecipitation; BRG1-deficient lung cancers are selectively sensitive to ATR inhibition. Gain/loss-of-function genetic approaches, single-molecule replication fork analysis, quantitative mass spectrometry, co-immunoprecipitation, pharmacological ATR inhibition Cancer research High 32690724
2021 Neuronal stimulation induces a CaMKII-sensitive serine phosphorylation of BRG1; phosphorylation alters BRG1 interactions with the NuRD repressor complex and cohesin; non-phosphorylatable BRG1 (knockin) fails to efficiently induce activity-dependent genes, while phosphomimic BRG1 increases enhancer activity; these mutant mice display anxiety-like phenotypes. Site-directed mutagenesis knockin mice, co-immunoprecipitation, ChIP-seq, RNA-seq, behavioral testing Cell reports High 34260936
2021 SMARCA4-mutant cells show impaired transactivation and significantly reduced levels of histone demethylases KDM6A/UTX and KDM6B/JMJD3, with aberrant accumulation of H3K27me3; SMARCA4-mutant cells are highly dependent on these demethylases for viability, and KDM6 inhibition (GSK-J4) has strong antitumor effects in orthotopic SMARCA4-mutant lung cancer and SCCOHT models. Western blotting, pharmacological KDM6 inhibition (GSK-J4), orthotopic xenograft models, histone modification profiling Nature communications High 34262032
2022 SMARCA4 colocalizes with SOX10 at gene regulatory elements in diffuse midline glioma (DMG) cells; SMARCA4 chromatin binding is reduced upon depletion of SOX10 or the H3.3K27M mutation; SMARCA4 occupancy at H3K27ac+SOX10 enhancers is most reduced upon depleting H3.3K27M, indicating H3.3K27M epigenome reprogramming creates a dependency on SMARCA4 for gene expression. ChIP-seq, siRNA depletion, patient-derived xenograft models, loss-of-function genetic approaches Cancer discovery High 36305747
2022 OTUD6A deubiquitinase stabilizes BRG1 by erasing K27-linked polyubiquitination on BRG1 (and K11-linked polyubiquitination on AR); identified via mass spectrometry screening; OTUD6A is required for prostate cancer cell progression, and OTUD6A oligonucleotides suppress tumorigenesis in vivo. Mass spectrometry screening, co-immunoprecipitation, ubiquitination assay, in vivo xenograft/PDX models Communications biology High 35233061
2023 SMARCA4/2 loss represses GLUT1 expression, reducing glucose uptake and glycolysis while increasing dependency on oxidative phosphorylation; these cells upregulate SLC38A2 to import glutamine for fueling OXPHOS; alanine supplementation competes with glutamine for SLC38A2 import and selectively induces death in SMARCA4/2-deficient cancer cells, synergizing with OXPHOS inhibitors. CRISPR knockout, metabolic flux assays, glucose uptake assay, RNA-seq, patient-derived xenografts, alanine supplementation experiments Nature communications High 37210563

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 2861 17081983
2011 Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature genetics 1493 21378990
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2004 Large-scale characterization of HeLa cell nuclear phosphoproteins. Proceedings of the National Academy of Sciences of the United States of America 1159 15302935
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2005 Nucleolar proteome dynamics. Nature 934 15635413
2009 Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nature genetics 895 19198609
2004 A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nature cell biology 841 14743216
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
1996 Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. The EMBO journal 683 8895581
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1998 Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 623 9845365
1996 Diversity and specialization of mammalian SWI/SNF complexes. Genes & development 597 8804307
1993 BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature 583 8232556
1994 The retinoblastoma protein and BRG1 form a complex and cooperate to induce cell cycle arrest. Cell 556 7923370
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