Global Chromatin Changes resulting from Single Gene Inactivation – the Role of SMARCB1 in Malignant Rhabdoid Tumor
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ABSTRACT:
PROVIDER: PRJNA729982 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14537601_1.fastq.gz | Fastqsanger.gz | |||
| SRR14537601_2.fastq.gz | Fastqsanger.gz | |||
| SRR14537602_1.fastq.gz | Fastqsanger.gz | |||
| SRR14537602_2.fastq.gz | Fastqsanger.gz | |||
| SRR14537603_1.fastq.gz | Fastqsanger.gz |
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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.
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Project description:Germline mutations of the SMARCB1 gene predispose to two distinct tumor syndromes: rhabdoid tumor predisposition syndrome, with malignant pediatric tumors mostly developing in brain and kidney, and familial schwannomatosis, with adulthood benign tumors involving cranial and peripheral nerves. The mechanisms by which SMARCB1 germline mutations predispose to rhabdoid tumors versus schwannomas are still unknown. Here, to understand the origin of these two types of SMARCB1-associated tumors, we generated different tissue- and developmental stage-specific conditional knockout mice carrying Smarcb1 and/or Nf2 deletion. Smarcb1 loss in early neural crest was necessary to initiate tumorigenesis in the cranial nerves and meninges with typical histological features and molecular profiles of human rhabdoid tumors. By inducing Smarcb1 loss at later developmental stage in the Schwann cell lineage, in addition to biallelic Nf2 gene inactivation, we generated the first mouse model developing schwannomas with the same underlying gene mutations found in schwannomatosis patients.
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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.
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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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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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