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Pooled CRISPR screens with joint single-nucleus chromatin accessibility and transcriptome profiling

ABSTRACT: A high-throughput CRISPR screening platform with joint single nucleus chromatin accessibility, transcriptome, and guide RNA capture (MultiPerturb-seq) using combinatorial indexing combined with droplet microfluidics to scale throughput and integrate all three modalities. We apply MultiPerturb-seq to identify key genes whose loss can trigger differentiation in a rare pediatric cancer, atypical teratoid/rhabdoid tumor (AT/RT), driven by loss of the SWI/SNF chromatin remodeling subunit SMARCB1.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE277747 | GEO | 2024/09/22

REPOSITORIES: GEO

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Pooled CRISPR screens with joint single-nucleus chromatin accessibility and transcriptome profiling [CUT&RUN]

Project description:A high-throughput CRISPR screening platform with joint single nucleus chromatin accessibility, transcriptome, and guide RNA capture (MultiPerturb-seq) using combinatorial indexing combined with droplet microfluidics to scale throughput and integrate all three modalities. We apply MultiPerturb-seq to identify key genes whose loss can trigger differentiation in a rare pediatric cancer, atypical teratoid/rhabdoid tumor (AT/RT), driven by loss of the SWI/SNF chromatin remodeling subunit SMARCB1.

2024-10-13 | GSE278910 | GEO

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

Mouse Smarcb1-deficient models recapitulate subtypes of human rhabdoid tumors.

Project description:Rhabdoid Tumors (RT) are highly aggressive tumors that are frequently localized in the central nervous system (CNS) where they are termed atypical teratoid and rhabdoid tumors (ATRT). We generated conditional Smarcb1-deficient mouse model leads to CNS Smarcb1-deficient tumors. We used microarrays to compared gene expression profilings of various human and mouse tumors. Our data demonstrate that the Smarcb1-deficient mouse model recapitulates the diversity of human RT.

2016-01-27 | GSE64019 | GEO

RNA sequencing data from primary atypical teratoid rhabdoid tumor (ATRT) samples

Project description:Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. The purpose of this study was to compare the transcriptomes of ATRTs with SMARCA4 mutations to those carrying SMARCB1 mutations.

2020-12-18 | GSE160748 | GEO

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

2013-12-31 | GSE46017 | GEO

Genome-wide DNA methylation profiling of SCCOHT and SMARCB1-mutated rhabdoid tumours

Project description:Extracranial rhabdoid tumours (ECRT) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRT_SMARCB1) but, rarely, ECRT can harbour the alternative inactivation of SMARCA4 (ECRT_SMARCA4) instead of SMARCB1. To explore the place of ECRTSMARCA4 in the "rhabdoid tumour" spectrum, we generated and collected from previous studies genome-wide DNA methylation array data (n = 85) from Atypical/Teratoid Rhabdoid Tumours (ATRT), ECRT_SMARCB1, ECRT_SMARCA4 and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) tumours. Using dimensionality reduction and unsupervised clustering approaches, our results demonstrate that ECRT_SMARCA4 display an intermediate DNA methylation profile between SCCOHT and ECRT_SMARCB1.

2021-06-02 | GSE175892 | GEO

SMARCB1 loss induces druggable cyclin D1 deficiency via upregulation of MIR17HG in atypical teratoid rhabdoid tumors

Project description:Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to rhabdoid tumor family usually caused by biallelic inactivation of SMARCB1, encoding a key subunit of SWI/SNF chromatin remodelling complexes. Previous studies proposed that SMARCB1 loss drives rhabdoid tumor by promoting cell cycle through activating transcription of cyclin D1 while suppressing p16. However, low cyclin D1 protein expression is observed in most ATRT patient tumors. The underlying mechanism and therapeutic implication of this molecular trait remain unknown. Here, we show that SMARCB1 loss in ATRT leads to the reduction of cyclin D1 expression by upregulating MIR17HG, a microRNA (miRNA) cluster known to generate multiple miRNAs targeting CCND1. Furthermore, we find that this cyclin D1 deficiency in ATRT results in marked in vitro and in vivo sensitivity to the CDK4/6 inhibitor palbociclib as a single agent. Our study identifies a novel genetic interaction between SMARCB1 and MIR17HG in regulating cyclin D1 in ATRT and suggests a rationale to treat ATRT patients with FDA-approved CDK4/6 inhibitors.

2020-06-08 | GSE147851 | GEO

Gene expression data from ATRT tumor samples

Project description:Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large series of human ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets. 49 ATRT samples were selected for RNA extraction and hybridization on Affymetrix Affymetrix Human Genome U133 Plus 2.0 Arrays. ---------------------------------------- This submission consists of the expression data for 49 of 170 samples only

2016-03-02 | E-GEOD-70678 | biostudies-arrayexpress

Natural and cryptic peptides dominate the immunopeptidome of atypical teratoid rhabdoid tumors.

Project description:Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS-tumors of infancy and early childhood. Hallmark is the surprisingly simple genomics with a truncating mutation in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T-cells. However, it is unclear, what T-cells might recognize on AT/RT cells. Here, we report a comprehensive analysis of naturally presented HLA-class-I and class-II ligands on n=23 AT/RTs. MS-based analysis of the HLA-ligandome revealed 55 class-I and 139 class-II peptides from tumor-associated proteins.

2022-05-31 | PXD033935 | Pride

Scalable pooled CRISPR screens with single cell chromatin accessibility profiling.

Project description:A scalable, cost-effective method that combines CRISPR perturbations with a single-cell indexing assay for transposase-accessible chromatin (CRISPR-sciATAC). This method links genome-wide chromatin accessibility to genetic perturbations through simultaneous capture of ATAC-seq fragments and CRISPR guide RNAs from single cells using a 96-well plate combinatorial indexing approach.

2020-11-07 | GSE161002 | GEO

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