Genomic characterization of SMARCA4 mutants in lung cancer
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ABSTRACT:
PROVIDER: PRJNA605122 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11033500_1.fastq.gz | Fastqsanger.gz | |||
| SRR11033500_2.fastq.gz | Fastqsanger.gz | |||
| SRR11033501_1.fastq.gz | Fastqsanger.gz | |||
| SRR11033501_2.fastq.gz | Fastqsanger.gz | |||
| SRR11033502_1.fastq.gz | Fastqsanger.gz |
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Project description:Using ATAC-seq, we identified the accessibility changes in lung cancer cells (NCI-H1944) reconstituted with SMARCA4 WT or SMARCA4 mutants. We also determined the SMARCA2-regulated accessibility program in NCI-H1944 after SMARCA2 depletion. Lastly, we identified the SMARCA2 accessibility program that is rescued by SMARCA4 WT and mutants. The "SAMPLE_ID" sample characteristic is a sample identifier internal to Genentech.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Using ChIP-seq, we identified the genome-wide occupancy of SMARCA2 and SMARCA4 in lung cancer cells (NCI-H1944) reconstituted with SMARCA4 WT. We also determined how SMARCA4 occupancy changed in NCI-H1944 after SMARCA2 depletion.
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Project description:SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 alterations on lung cancer initiation and progression remain poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient tumors lack lung lineage transcription factor activities and instead show activation of embryonic stem cell-like programs, resembling a metastatic cell state. Thus, the SWI/SNF complex – via Smarca4 – acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.
2021-09-07 | GSE161920 | GEO
Project description:SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 alterations on lung cancer initiation and progression remain poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient tumors lack lung lineage transcription factor activities and instead show activation of embryonic stem cell-like programs, resembling a metastatic cell state. Thus, the SWI/SNF complex – via Smarca4 – acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.
2021-09-07 | GSE180817 | GEO
Project description:SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 mutation on tumor initiation, progression and chromatin regulation in lung cancer remains poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung in a cell-type dependent fashion to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient primary tumors lack lung lineage transcription factor activities and instead show hyper-activation of embryonic stem cell-like programs, resembling a metastatic cell state. Mechanistically, we show that all three classes of SWI/SNF complexes are unable to bind and open chromatin at distinct regulatory regions in the absence of SMARCA4, thereby preventing lineage factors from binding to their targets and maintaining cell identity – ultimately accelerating tumor progression. Thus, the SWI/SNF complex – via Smarca4 – acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.
2021-09-07 | GSE164857 | GEO
Project description:SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 mutation on tumor initiation, progression and chromatin regulation in lung cancer remains poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung in a cell-type dependent fashion to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient primary tumors lack lung lineage transcription factor activities and instead show hyper-activation of embryonic stem cell-like programs, resembling a metastatic cell state. Mechanistically, we show that all three classes of SWI/SNF complexes are unable to bind and open chromatin at distinct regulatory regions in the absence of SMARCA4, thereby preventing lineage factors from binding to their targets and maintaining cell identity – ultimately accelerating tumor progression. Thus, the SWI/SNF complex – via Smarca4 – acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.
2021-09-07 | GSE164820 | GEO
Project description:SMARCA4 (BRG1) encodes for one of two mutually-exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes, and is among the most frequently mutated genes in human lung adenocarcinoma. Despite its prevalence, the functional consequences of SMARCA4 mutation on tumor initiation, progression and chromatin regulation in lung cancer remains poorly understood. Using genetically engineered mouse models, patient-derived xenografts, and single-cell epigenomic profiling, we demonstrate that loss of Smarca4 sensitizes CCSP+ cells within the lung in a cell-type dependent fashion to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient primary tumors lack lung lineage transcription factor activities and instead show hyper-activation of embryonic stem cell-like programs, resembling a metastatic cell state. Mechanistically, we show that all three classes of SWI/SNF complexes are unable to bind and open chromatin at distinct regulatory regions in the absence of SMARCA4, thereby preventing lineage factors from binding to their targets and maintaining cell identity – ultimately accelerating tumor progression. Thus, the SWI/SNF complex – via Smarca4 – acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution.
2021-09-07 | GSE164770 | GEO
Project description:Purpose: The purpose of this study was to develop a framework for analyzing RPE expression profiles from zebrafish eye mutants. Methods: The fish model we used was smarca4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4), a retinal dystrophic mutant that the retinal phenotype and expression profiles were previously characterized. Histological and Affymetrix GeneChip analyses were conducted to define the RPE defects and underlying differential expression respectively. Results: Histological analysis indicates that smarca4 RPE was formed but its differentiation was abnormal. In particular, ultra-structural analysis of smarca4 RPE by transmission electron microscopy showed a number of defects in melanogenesis, suggesting that the cytoskeletal dynamics was impaired. To compare the expression profile of normal wild-type (WT) and smarca4 RPE, their retinas and RPE-attached retinas were microdissected and the gene expression values of these tissues measured by Affymetrix GeneChip analysis. The RPE expression values were then estimated from these samples using an approach previously established by us. A factorial analysis was conducted using the expression values of RPE, retinal as well as the whole-embryo samples. Specific rules (contrasts) were built using the coefficients of the resulting fitted model to select for three groups of genes: 1) Smarca4-regulated RPE genes, 2) Smarca4-regulated retinal genes, and 3) Smarca4-regulated RPE genes that are not differentially expressed in the retina. The latter group consists of 39 genes that are highly related to cytoskeletal dynamics, melanogenesis, paracrine and intracellular signal transduction. Conclusions: Our analytical framework can potentially identify genes in zebrafish mutants that both retina and RPE are affected by the underlying mutation. The gene expression levels of three independent replicates of WT whole embryos (WA52), WT retinas (WR52), WT RPE-attached retinas (WRR52), smarca4/yng retinas (YR52), smarca4 RPE-attached retinas (YRR52) and smarca4 whole embryos (YA52) were measured by Affymetrix Zebrafish Whole Genome Arrays. All samples were collected at 52 hpf. The probe-level data of these sample groups were background adjusted, normalized and summarized by a robust multiarray average (RMA) algorithm. RPE expression values were estimated from the comparison between the retinal and RPE-attached retinal samples of the same genotype based on a method we previously developed (Leung et al., Invest Ophthalmol Vis Sci. 2007; 48:881). Then, a 3x2 factorial design was used to analyze the expression values of three kinds of tissue (T): whole embryo, retina and RPE in two kinds of mutation (M) background: WT and smarca4. Using the coefficients from the fitted models, contrasts were built to identify candidate genes that fulfilled specific criteria. The false discovery rate (FDR) q-value cutoff for a contrast was 0.001. Several contrasts were ultimately combined to allow for selection of genes that were regulated by Smarca4 in the retina and RPE. These include 1) Smarca4-regulated RPE genes, 2) Smarca4-regulated retinal genes, and 3) Smarca4-regulated RPE genes that are not differentially expressed in the retina.
2014-01-03 | E-GEOD-50241 | biostudies-arrayexpress