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Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

ABSTRACT: SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development.

ORGANISM(S): Mus musculus

PROVIDER: GSE46017 | GEO | 2013/12/31

SECONDARY ACCESSION(S): PRJNA196906

REPOSITORIES: GEO

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Transcriptional response to Smarcb1 re-expression in murine derived Smarcb1 deficient p53 null tumors

Project description:SMARCB1 (Snf5/Ini1/Baf47) is a potent tumor suppressor, the loss of which serves as the diagnostic feature in Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms. Here, we restore Smarcb1 expression in cells derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice. Profiling Smarcb1 dependent gene expression we find genes which are dependent on Smarcb1 expression to be enriched for ECM and cell adhesion functions. We identify Igfbp7, which is related to the insulin-like growth factor binding proteins family, as a downstream target of Smarcb1 transcriptional activity, and show that re-introduction of Igfbp7 alone can hinder tumor development. Two cancer cell lines, 167 and 365, derived from Smarcb1-deficient tumors which developed in Smarcb1-heterozygous p53-/- mice were re-infected with a retro-viral vector for Smarcb1 re-expression or an empty retro-viral vector as control. Total-RNA was collected 3 days post infection so as to enrich for direct targets of Smarcb1 transcriptionaly regulated genes

2013-12-31 | E-GEOD-46017 | biostudies-arrayexpress

SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [primary tissue_ChIP-seq]

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

SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [cell line_RNA-seq]

2016-11-21 | GSE71505 | GEO

SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [cell line_ChIP-seq]

2016-11-21 | GSE71504 | GEO

SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [primary tissue_RNA-seq]

2016-11-21 | GSE71503 | GEO

Inhibition of MYC by the SMARCB1 tumor suppressor

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

SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters [ChIP-Seq]

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

SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters [RNA-Seq]

2017-09-25 | GSE90633 | GEO

SMARCB1 is required for widespread BAF complex-mediated activation of enhancers and bivalent promoters [Hi-C]

2017-09-25 | GSE90632 | GEO

Global Chromatin Changes resulting from Single Gene Inactivation – the Role of SMARCB1 in Malignant Rhabdoid Tumor

Project description:Human cancer typically results from the stochastic accumulation of multiple oncogene-activating and tumors suppressor gene inactivating mutations, however this process takes time and especially in the context of certain pediatric cancer, fewer but more ‘impactful’ mutations may in short order produce the full-blown cancer phenotype. This is well-exemplified by the highly aggressive malignant rhabdoid tumor (MRT), where the only gene classically showing recurrent inactivation is SMARCB1, a subunit member of the BAF chromatin remodeling complex. This is true of all three presentations of MRT including MRT of kidney (MRTK), MRT of the central nervous system (Atypical Teratoid Rhabdoid Tumor – ATRT) and Extracranial, Extrarenal Rhabdoid Tumor (EERT). Our reverse modeling of rhabdoid tumors with isogenic cell lines, either induced or not induced, to express SMARCB1 showed widespread differential chromatin remodeling indicative of altered BAF complex activity with ensuant histone modifications when tested by chromatin immunoprecipitation followed by sequencing (ChIP-seq). The changes due to reintroduction of SMARCB1 were preponderantly at typical enhancers with tandem BAF complex occupancy at these sites and related gene activation, as substantiated also by transcriptomic data. Indeed, for both MRTK and ATRT cells, there is evidence of an overlap between SMARCB1-dependent enhancer activation and tissue-specific lineage determining genes. These genes are inactive in the tumor state, conceivably arresting the cells in a primitive/undifferentiated state. This epigenetic dysregulation from inactivation of a chromatin remodeling complex subunit contributes to an improved understanding of the complex pathophysiological basis of MRT, one of the most lethal and aggressive human cancers.

2021-05-15 | GSE174446 | GEO

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