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SMARCB1 loss creates patient-specific MYC topologies that drive malignant rhabdoid tumor growth [Hi-C]

ABSTRACT: Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer. Yet, their contribution to tumorigenesis remains in many cases poorly understood. Here, we studied derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 drives patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE218113 | GEO | 2023/10/20

REPOSITORIES: GEO

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SMARCB1 loss creates patient-specific MYC topologies that drive malignant rhabdoid tumor growth [ChIP-seq]

Project description:Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer. Yet, their contribution to tumorigenesis remains in many cases poorly understood. Here, we studied derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 drives patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

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SMARCB1 loss creates patient-specific MYC topologies that drive malignant rhabdoid tumor growth [ATAC-seq]

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SMARCB1 loss creates patient-specific MYC topologies that drive malignant rhabdoid tumor growth

Project description:Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Here, we studied derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene and validation of this data in patients with combined single-cell RNA-seq and ATAC-seq.

2023-10-19 | GSE218385 | GEO

SMARCB1 loss creates patient-specific MYC topologies that drive malignant rhabdoid tumor growth

Project description:Malignant rhabdoid tumor (MRT) is a highly malignant and often lethal childhood cancer. MRTs are genetically defined by bi-allelic inactivating mutations in SMARCB1, a member of the BRG1/BRM-associated factors (BAF) chromatin remodeling complex. Mutations in BAF complex members are common in human cancer, yet their contribution to tumorigenesis remains in many cases poorly understood. Here, we studied derailed regulatory landscapes as a consequence of SMARCB1 loss in the context of MRT. Our multi-omics approach on patient-derived MRT organoids revealed a dramatic reshaping of the regulatory landscape upon SMARCB1 reconstitution. Chromosome conformation capture experiments subsequently revealed patient-specific looping of distal enhancer regions with the promoter of the MYC oncogene. This intertumoral heterogeneity in MYC enhancer utilization is also present in patient MRT tissues as shown by combined single-cell RNA-seq and ATAC-seq. We show that loss of SMARCB1 drives patient-specific epigenetic reprogramming underlying MRT tumorigenesis.

| EGAS00001007590 | EGA

Transcriptomic data of established human AT/RT cell lines BT-12.

Project description:The multi-subunit ATP-dependent chromatin remodeling complex BAF ('mammalian SWI/SNF complex') regulates DNA accessibility during cell fate transitions and functions as a context-dependent tumor suppressor. SMARCB1, as a one of the component of BAF complex, was first found to be biallelically inactivated in ~98% of all malignant rhabdoid tumors (MRT), aggressive pediatric tumors that can occur cranially or extracranially. To examine the mechanisms through which inactivation of SMARCB1 drives malignant rhabdoid tumorigenesis, we conducted RNAseq studies in BT-12 cells reconstituted with either WT or M4 mutant (an in-frame deletion (185-193D) was identified from tumor patient) SMARCB1. These results indicate that loss of SMARCB1 promotes cell proliferation but also impairs cell adhesion and migration, consistent with the hypothesis that SMARCB1 exerts its tumor suppressive function predominantly by inhibiting proliferation. We applied the RNA-Seq to provide the transcriptomic profiling of BT-12 cell lines without or with stable expression of SMARCB1.

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Project description:We report that the protein encoded by the SMARCB1 gene, SNF5, is capable of inhibiting MYC binding in vitro and in a malignant rhabdoid tumor (MRT) cell line. By comparing the effects of reintroduction of SNF5 with genetic inhibition of MYC (OMOMYC) on multiple aspects of chromatin remodeling and transcription in MRT cells, we show that regulation of MYC binding by SNF5 is not connected to the role of SNF5 in chromatin remodeling, but instead is responsible for controlling RNA polymerase pause release during transcription. Our data reveal that SNF5 negatively regulates MYC function and may explain how loss of SNF5 can lead to rapid tumorigenesis.

2019-04-12 | GSE109310 | GEO

Integrative analyses of rhabdoid tumors across all anatomical sites reveal subgroups with possible immune modulation through epigenetic dysregulation

Project description:Extra-cranial malignant rhabdoid tumors (MRTs) and cranial atypical teratoid RTs (ATRTs) are pediatric cancers driven by SMARCB1 loss. To understand biological relationships between MRTs and ATRTs, we performed integrative data analyses of 140 MRTs and 161 ATRTs, and detected features conserved between MRTs and the MYC subgroup of ATRTs, including global DNA hypomethylation and over-expression of HOX and mesenchymal development genes, thereby distinguishing them from other ATRT subgroups that exhibit neural-like features. Our analyses revealed five DNA-methylation subgroups associated with distinct anatomical sites, SMARCB1 alteration patterns, and distinct gene-expression and enhancer profiles. We also report on RT subgroups with expression patterns indicative of both increased immune infiltration and expression of immune checkpoint genes, which were confirmed using immunohistochemical techniques.

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