The effects of the loss of SMARCB1 on DNA damage repair
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE325741 | GEO | 2026/03/25
REPOSITORIES: GEO
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Project description:BAF complex perturbations contribute to over 20% of human cancer, yet the mechanisms by which these alterations drive oncogenesis remain poorly understood. The driving role for BAF complex mutations in cancer was first documented in malignant rhabdoid tumor (MRT), an aggressive pediatric cancer in which loss of SMARCB1 (also known as BAF47, INI1, hSNF5), a core BAF complex subunit, is the hallmark genetic alteration. We find that loss of BAF47 destabilizes the biochemical affinity of BAF complexes on chromatin without significantly impairing complex integrity or subunit composition. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in global increases in BAF complex occupancy, which mediates a major gain in enhancer activation. In addition, we find BAF47 targets BAF complexes to bivalent promoters, resolving bivalency to activation through opposition of polycomb-mediated repression. These findings demonstrate collaborative gene activation by the BAF complex through distinct mechanisms, highlighting specific BAF complex functions that are coopted or abated to drive human cancers and developmental disorders.
2017-09-25 | GSE90633 | GEO
Project description:BAF complex perturbations contribute to over 20% of human cancer, yet the mechanisms by which these alterations drive oncogenesis remain poorly understood. The driving role for BAF complex mutations in cancer was first documented in malignant rhabdoid tumor (MRT), an aggressive pediatric cancer in which loss of SMARCB1 (also known as BAF47, INI1, hSNF5), a core BAF complex subunit, is the hallmark genetic alteration. We find that loss of BAF47 destabilizes the biochemical affinity of BAF complexes on chromatin without significantly impairing complex integrity or subunit composition. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in global increases in BAF complex occupancy, which mediates a major gain in enhancer activation. In addition, we find BAF47 targets BAF complexes to bivalent promoters, resolving bivalency to activation through opposition of polycomb-mediated repression. These findings demonstrate collaborative gene activation by the BAF complex through distinct mechanisms, highlighting specific BAF complex functions that are coopted or abated to drive human cancers and developmental disorders.
2017-09-25 | GSE90632 | GEO
Project description:BAF complex perturbations contribute to over 20% of human cancer, yet the mechanisms by which these alterations drive oncogenesis remain poorly understood. The driving role for BAF complex mutations in cancer was first documented in malignant rhabdoid tumor (MRT), an aggressive pediatric cancer in which loss of SMARCB1 (also known as BAF47, INI1, hSNF5), a core BAF complex subunit, is the hallmark genetic alteration. We find that loss of BAF47 destabilizes the biochemical affinity of BAF complexes on chromatin without significantly impairing complex integrity or subunit composition. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in global increases in BAF complex occupancy, which mediates a major gain in enhancer activation. In addition, we find BAF47 targets BAF complexes to bivalent promoters, resolving bivalency to activation through opposition of polycomb-mediated repression. These findings demonstrate collaborative gene activation by the BAF complex through distinct mechanisms, highlighting specific BAF complex functions that are coopted or abated to drive human cancers and developmental disorders.
2017-09-25 | GSE90631 | GEO
Project description:Poorly-differentiated (PD) chordoma, a tumor found mainly in children, adolescents and young adults is a rare, aggressive tumor originating from notochordal tissue, with limited therapeutic options. SMARCB1, a core component of the BAF and PBAF chromatin remodeling complexes, is the most frequently mutated gene in PD chordomas, the most aggressive form of this cancer. In this study, we employed cellular models of SMARCB1-negative PD chordomas to characterize expression of SWI/SNF complex members and determine the impact of SMARCB1 re-expression on cell growth as well as the transcriptional landscape by RNA-seq. We generated 2 SMARCB1-negative PD chordoma cell lines, CH22 and UM-Chor5, with an inducible SMARCB1 expression system. After 72 hours of induction of SMARCB1 re-expression, we observed continued growth of both SMARCB1-negative PD chordoma cell lines. This is in striking contrast to SMARCB1-deficient rhabdoid cell lines, where we found SMARCB1 re-expression inhibits growth completely. We also found the lack of growth inhibition may arise from the loss of CDKN2A/p16INK4A expression in all poorly differentiated chordoma cell lines which correlated well with the gene expression data. SMARCB1 re-expression in both CH22 and UM-Chor5 cells showed downregulation for rRNA and RNA processing as well as metabolic processing. Upregulated differentially expressed genes included those involved in cell adhesion, cell migration, and development. Taken together, our data establish SMARCB1 re-expression in PD chordomas alters the repertoire of SWI/SNF complexes, perhaps restoring those associated with cellular differentiation. Our findings support a model where SMARCB1 inactivation blocks the conversion of growth-promoting SWI/SNF complexes to differentiation-inducing ones.
2022-12-21 | GSE217999 | GEO
Project description:We generated mouse tumors of each combination of genotypes that included either presence or absence of heterozygosity for hSS2 in Rosa26 and homozygosity for wildtype or floxed alleles of Smarcb1. In order to test how these different tumor genotypes impacted BAF distribution across the genome, we performed ChIPseq in tumors of each genotype for member components shared by all BAF subtypes, SMARCC1 (also named BAF155) and SMARCA4 (also named BRG1.) We also performed ChIPseq for RNAPOLII to determine the BAF relationship with transcription in each genotype. The length of peaks is extended in fusion-expressing tumors, regardless of Smarcb1 status. The heatmaps of SMARCC1 enrichments at transcription start sites (TSSs) across the genome in fusion-only tumors demonstrate a very similar overall pattern with that in combination genotype tumors, which suggested that the fusion plays a deterministic role in the distribution of BAF complexes across the genome. Specifically around each TSS across the genome was a striking absence of BAF enrichment in both groups that bore genetic silencing of Smarcb1, not present in the fusion-only group. This suggests that some SMARCB1-retaining BAF complex is necessary to permit binding to the TSS or the +1 nucleosome position. Fusion expression and Smarcb1 silencing have different impacts on BAF genomic locations.
2021-07-01 | GSE153857 | GEO
Project description:Using ChIP-seq technology, we aimed to provide insight into the consequences of the knockdown of Smarcb1, an essential esBAF subunit, for the binding of the esBAF complex (Smarca4), the PRC2 complex (Ezh2) as well as for histone marks H3K27me3, H3K27ac and H3K4me3. We show that Smarcb1 knockdown results in the change of BAF complex binding in both directions: decreased binding (potentially by loss of function) as well as increased binding (potentially by retargeting). Furthermore, we see that binding changes especially occur in regions important for basic cellular functions (adhesion, cell organization, metabolism) as well as regions crucial for development (especially nervous system development). In addition, we depicted binding changes in enhancer regions in which a decrease of BAF binding was much more prominent than in gene regions.
2022-04-27 | GSE186667 | GEO
Project description:SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human RTs show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.
2016-11-21 | GSE71503 | GEO
Project description:SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human RTs show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.
2016-11-21 | GSE71504 | GEO
Project description:SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human RTs show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.
2016-11-21 | GSE71505 | GEO
Project description:SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here, we show that despite indistinguishable mutational landscapes, human RTs show distinct enhancer H3K27ac signatures, which reveal remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared across all subtypes, such as SPRY1, and other lineage-specific super-enhancers like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1.
2016-11-21 | GSE71502 | GEO