The BAF complex blocks Myogenesis in rhabdomyosarcoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA680368 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13120811_1.fastq.gz | Fastqsanger.gz | |||
| SRR13120811_2.fastq.gz | Fastqsanger.gz | |||
| SRR13120812_1.fastq.gz | Fastqsanger.gz | |||
| SRR13120812_2.fastq.gz | Fastqsanger.gz | |||
| SRR13120813_1.fastq.gz | Fastqsanger.gz |
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Project description:Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer of skeletal muscle lineage. The aggressive alveolar subtype is commonly characterized by t(2;13) or t(1;13) translocations with the expression of PAX3- or PAX7-FOXO1 fusion transcription factors respectively and is known as fusion positive RMS (FP-RMS). FP-RMS tumors rely on the fusion gene to maintain their proliferative state while avoiding terminal differentiation program. Since disruptions of normal development are likely governed by epigenetic changes in these low-mutational-burden tumors, we investigated the contributions of chromatin regulatory complexes to RMS tumor maintenance. We demonstrate the essentiality of the mSWI/SNF ATPase BRG1 for FP-RMS proliferation and discover that RMS significantly overexpress SMARCA4 (encoding BRG1) compared to skeletal muscle. We define the mSWI/SNF subunit repertoire in FP-RMS and provide evidence for the assembly of multiple mSWI/SNF complexes including canonical BAF, PBAF and non-canonical (nc)BAF in FP-RMS. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which was further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with FP-RMS core regulatory transcription factors. We report that mSWI/SNF complexes act as sensors of chromatin state, which are recruited to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes. Finally, BRG1 targeting compounds reproduce the effects of genetic ablation. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for treating this lethal childhood tumor.
2021-04-01 | GSE162052 | GEO
Project description:Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer of skeletal muscle lineage. The aggressive alveolar subtype is commonly characterized by t(2;13) or t(1;13) translocations with the expression of PAX3- or PAX7-FOXO1 fusion transcription factors respectively and is known as fusion positive RMS (FP-RMS). FP-RMS tumors rely on the fusion gene to maintain their proliferative state while avoiding terminal differentiation program. Since disruptions of normal development are likely governed by epigenetic changes in these low-mutational-burden tumors, we investigated the contributions of chromatin regulatory complexes to RMS tumor maintenance. We demonstrate the essentiality of the mSWI/SNF ATPase BRG1 for FP-RMS proliferation and discover that RMS significantly overexpress SMARCA4 (encoding BRG1) compared to skeletal muscle. We define the mSWI/SNF subunit repertoire in FP-RMS and provide evidence for the assembly of multiple mSWI/SNF complexes including canonical BAF, PBAF and non-canonical (nc)BAF in FP-RMS. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which was further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with FP-RMS core regulatory transcription factors. We report that mSWI/SNF complexes act as sensors of chromatin state, which are recruited to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes. Finally, BRG1 targeting compounds reproduce the effects of genetic ablation. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for treating this lethal childhood tumor.
2020-11-20 | MSV000086494 | MassIVE
Project description:Rhabdomyosarcomas (RMSs) are the most frequent soft tissue sarcomas in children that share many features of developing skeletal muscle. We have discovered that a T-box family member, TBX2, is highly upregulated in tumor cells of both major RMS subtypes. TBX2 is a repressor that is often overexpressed in cancer cells and is thought to function in bypassing cell growth control, including repression of p14 and p21. The cell cycle regulator p21 is required for the terminal differentiation of skeletal muscle cells and is silenced in RMS cells. We have found that TBX2 interacts with the myogenic regulatory factors MyoD and myogenin and inhibits the activity of these factors. TBX2 is expressed in primary myoblasts and C2C12 cells, but is strongly downregulated upon differentiation. TBX2 recruits the histone deacetylase HDAC1 and is a potent inhibitor of the expression of muscle-specific genes and the cell cycle regulators, p21 and p14. TBX2 promotes the proliferation of RMS cells and either depletions of TBX2 or dominant negative TBX2 upregulate p21- and muscle-specific genes. Significantly, depletion or interference with TBX2 completely inhibits tumor growth in a xenograft assay, highlighting the oncogenic role of TBX2 in RMS cells. Thus, the data demonstrate that elevated expression of TBX2 contributes to the pathology of RMS cells by promoting proliferation and repressing differentiation-specific gene expression. These results show that deregulated TBX2 serves as an oncogene in RMS, suggesting that TBX2 may serve as a new diagnostic marker or therapeutic target for RMS tumors.
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Project description:Mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes play critical roles in governing genomic architecture and gene expression and are frequently perturbed in human cancers. Transcription factors (TFs), including fusion oncoproteins, can bind to BAF complex surfaces to direct chromatin targeting and accessibility, often activating oncogenic gene loci. Here, we demonstrate that the FUS-DDIT3 fusion oncoprotein hallmark to myxoid liposarcoma (MLPS) inhibits BAF complex-mediated remodeling of adipogenic enhancer sites via sequestration of the adipogenic TF, CEBPB, from the genome. In mesenchymal stem cells, small molecule inhibition of BAF complex ATPase activity attenuates adipogenesis via failure of BAF-mediated DNA accessibility and gene activation at CEBPB target sites genome-wide. BAF chromatin targeting and gene expression profiles of FUS-DDIT3-expressing cell lines and primary tumors exhibit similarity to SMARCB1-deficient BAF loss-of-function tumor types. These data present a novel mechanism by which fusion oncoproteins generate BAF complex loss-of-function phenotypes, independent of deleterious subunit mutations.
2022-04-18 | GSE179720 | 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: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:Aberrations in genes coding for subunits of the BAF chromatin remodeling complex are highly abundant in human cancers. Currently, it is not understood how these loss-of-function mutations contribute to cancer development and how they can be targeted therapeutically. The cancer type specific occurrence patterns of certain subunit mutations suggest subunit-specific effects on BAF complex function, possibly by the formation of aberrant residual complexes. Here, we systematically characterize the effects of individual subunit loss on complex composition, chromatin accessibility and gene expression in a panel of knock-out cell lines deficient for 22 targetable BAF subunits. We observe strong, specific and often discordant alterations dependent on the targeted subunit and show that these explain intra-complex co-dependencies, including the novel synthetic lethal interactions SMARCA4-ARID2, SMARCA4-ACTB and SMARCC1-SMARCC2. These data provide insights into the role of different BAF subcomplexes in genome-wide chromatin organization and suggest novel approaches to therapeutically target BAF mutant cancers.
2019-08-01 | PXD013102 | Pride
Project description:We conducted a screening for nuclear proteins which interact with α-synuclein by mass-spectrometry. As a result, we found that α-synuclein interact with BAF complex. Furthermore, overexpressed α-synuclein increased global H4R3me2s by promoting interaction between BAF complex and PRMT5 in cultered cells. In this study, we explored the influence of overexpressed α-synuclein on H4R3me2s by ChIP-seq using anti-H4R3me2s antibody.
2023-11-23 | GSE228331 | GEO
Project description:The BAF complex does not mediate GLI repression
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