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Gene expression analysis of human haploid cells (HAP1) depleted of SMARCB1 and SMARCA4

ABSTRACT: The aim of this study is to analyze the change in genome wide expression levels in HAP1 cells upon loss of SMARCB1, SMARCA4 or both these genes together. The SMARCB1 and SMARCA4 genes were the hits from a genome wide screen involving genetrap mutagenesis to find new players that are involved in sensitivity to Doxorubicin (Dox). It was found that loss of SMARCB1 and SMARCA4 genes impart resistance in HAP1 cells to Dox. To validate this, the genes were knocked out in HAP1 cells with CRISPR-Cas9 technology. Gene expression levels in SMARCB1 null, SMARCA4 null and SMARCB1-SMARCA4 double null cells were compared to wildtype HAP1 cells using RNAseq. From these experiments it was found that SMARCB1 loss caused several fold increase in ABCB1 gene levels. ABCB1 is an efflux pump in cells responsible for flushing out many small-molecule drugs. Further analysis of this gene confirmed that ABCB1 was the main factor responsible for Dox resistance upon SMARCB1 loss.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75515 | GEO | 2016/08/22

SECONDARY ACCESSION(S): PRJNA304449

REPOSITORIES: GEO

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Gene expression analysis of human haploid cells (HAP1) depleted of SMARCB1 and SMARCA4

Project description:The aim of this study is to analyze the change in genome wide expression levels in HAP1 cells upon loss of SMARCB1, SMARCA4 or both these genes together. The SMARCB1 and SMARCA4 genes were the hits from a genome wide screen involving genetrap mutagenesis to find new players that are involved in sensitivity to Doxorubicin (Dox). It was found that loss of SMARCB1 and SMARCA4 genes impart resistance in HAP1 cells to Dox. To validate this, the genes were knocked out in HAP1 cells with CRISPR-Cas9 technology. Gene expression levels in SMARCB1 null, SMARCA4 null and SMARCB1-SMARCA4 double null cells were compared to wildtype HAP1 cells using RNAseq. From these experiments it was found that SMARCB1 loss caused several fold increase in ABCB1 gene levels. ABCB1 is an efflux pump in cells responsible for flushing out many small-molecule drugs. Further analysis of this gene confirmed that ABCB1 was the main factor responsible for Dox resistance upon SMARCB1 loss. In total there are four different cell types with two replicates for each cell type. Therefore, 8 samples in total.

2016-08-22 | E-GEOD-75515 | biostudies-arrayexpress

Homo sapiens

Project description:Gene expression analysis of human haploid cells (HAP1) depleted of SMARCB1 and SMARCA4

| PRJNA304449 | ENA

Transcriptional chracterization of ABCC1 and ABCB1 KO and MZ1 treated WT HAP1 cell lines.

Project description:We used CRISPR/Cas9 to intoroduce frame-shifting mutations into the ABCC1 and ABCB1 genes and treated HAP1 WT cells with varying concentrations of the MZ1 PROTAC. To measure the transcriptional response to both genetic and chemical perturbances, we performed RNA-seq and quantified gene expression levels.

2023-06-07 | GSE234043 | GEO

siRNA Knockdown of SWI/SNF complex proteins in prostate cancer cell lines

Project description:Here we performed transcriptional profiling of the prostate cancer cell lines LNCaP and 22Rv1 comparing non-targeting siRNA treatment versus siRNAs targeting SWI/SNF complex proteins (SMARCA2, SMARCA4, and SMARCB1). Goal was to determine the effect of SWI/SNF knockdown on gene expression in prostate cancer. Two-condition experiment: non-targeting siRNA versus SWI/SNF-siRNA treated cells. Three SWI/SNF proteins were targeted: SMARCA2, SMARCA4, and SMARB1. Biological replicates: 1 control replicate, 2 treatment replicates per SWI/SNF protein. Technical replicates: 1 replicate per SWI/SNF protein. Cell lines: 22Rv1 and LNCaP.

2013-07-20 | E-GEOD-40384 | biostudies-arrayexpress

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

Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [WES]

Project description:SWI/SNF ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here we developed AU-24118, a first-in-class, orally bioavailable degrader of SMARCA2/4 and PBRM1. AU-24118 demonstrated tumor regression in a castration resistant model of prostate cancer which was further enhanced in combination with enzalutamide. Prostate cancer cell lines exposed to increasing doses of a SWI/SNF degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. While SMARCA4 mutations provided specific resistance to SWI/SNF degraders, ABCB1 overexpression provided broader resistance to other compounds as well as could be overcome with ABCB1 inhibition.

2024-03-15 | GSE250327 | GEO

Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [RNA-seq]

2024-03-15 | GSE250326 | GEO

Gene expression profile of MX-1 breast cancer cell line and chemoresistant sublines of them

Project description:Breast cancer is a leading cause of cancer-related deaths among women in the Western world. Anthracyclines, including doxorubicin (DOX), along with taxanes, cyclophosphamide and platinum compounds are the main chemotherapeutic agents applied for breast cancer treatment. However, chemoresistance is the major cause of the disease progression following chemotherapy. Drug resistance can be either inherent or acquired during the treatment, but most possibly the interaction of both mechanisms drives the rapid development of treatment refractory cancer. In the present study, the mechanisms of acquired cellular chemoresistance were studied in breast cancer cell line MX-1 exposed to gradually increasing concentration of the chemotherapeutic compound DOX (MX-1/D). Nongenotoxic phosphorganic compound tetraphenylphosphonium cation (TPP+) – a potent substrate and activator for ABCB1 transporter – was used in the cell line model of intrinsic chemoresistance (MX-1/T). Finally, DOX highly resistant cell subline was derived from ABCB1-activated, TPP+ pretreated cells (MX-1/TD). Chemoresistance in all cell sublines was closely associated with the EMT, and the ABCB1 hyperexpression was a possibly trigger of this process.

2020-12-30 | GSE163986 | 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

mSWI/SNF functional genomic characterization of SMARCB1 mutants in SMARCB1-null and heterozygous settings

Project description:Chromatin remodeling complexes regulate gene expression by shifting, evicting, and exchanging nucleosomes along the chromosomes of eukaryotic organisms. The mammalian SWI/SNF chromatin remodeling complex (mSWI/SNF or BAF) is mutated in over 20% of human cancers and loss of the SMARCB1 gene, encoding the BAF47 protein subunit, results in one of the most aggressive and lethal pediatric cancers. An accumulation of point mutations occurs at the C-terminal end of the protein, for which the functional ramifications are unknown. We previously demonstrated that reintroduction of SMARCB1 in SMARCB1-null malignant rhabdoid tumor cells results in a genome-wide increase of mSWI/SNF complex occupancy coupled with activation of PRC2-repressed genes. Here, we study the functional consequences that these point mutations exert on mSWI/SNF complex activity in SMARCB1-deficient tumor cells and extend this investigation to a CRISPR/Cas9-mediated SMARCB1-heterozygous mutant induced pluripotent stem cell. Intriguingly, we observe that the mutant complexes bind similarly to wild-type SMARCB1 complexes at enhancers throughout the genome but often fail to transcriptionally activate nearby genes in a cis-regulatory manner.

2019-11-21 | GSE124903 | GEO

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