SMARCB1 maintains lineage fidelity in renal cancer.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA760343 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15712100.fastq.gz | Fastqsanger.gz | |||
| SRR15712101.fastq.gz | Fastqsanger.gz | |||
| SRR15712102.fastq.gz | Fastqsanger.gz | |||
| SRR15712103.fastq.gz | Fastqsanger.gz | |||
| SRR15712104.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:SMARCB1 maintains lineage fidelity in renal cancer - ATAC-seq
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Project description:SMARCB1 maintains lineage fidelity in renal cancer - RNA-seq
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Project description:Transcriptional lineage factors are a prominent class of essential genes in cancer, but the mechanisms that maintain lineage fidelity in advanced cancer clones, and whether lineage factor pathways could be broadly exploited for cancer therapy remain poorly understood. Here, we have used clear cell renal cell carcinoma (ccRCC) as a model to characterise the mechanisms that underlie lineage factor dependence in cancer. Through CRISPR/Cas9 loss-of-function screening and functional validation we find that loss of SMARCB1, a member of the SWI/SNF chromatin remodelling complex, can confer an advantage to ccRCC cells upon inhibition of the essential renal lineage factor PAX8. PAX8 inhibition resistant cells formed tumours with a dramatically altered histology showing neuroendocrine differentiation. Based on ATAC-seq and RNA-seq analysis, SMARCB1 inactivation leads to large-scale loss of kidney-specific epigenetic programmes, acquisition of a cellular state resembling that of rhabdoid tumours, and eventual activation of proliferative pathways. We show that these pathways are supported by the adoption of new transcriptional dependencies on IRF2, BHLHE40, and ZNFX1, factors that represent rare essential genes across different lineage-specific and oncogenic pathways, a principle validated in a large-scale CRISPR/Cas9 screening data set comprising hundreds of cancer cell lines. Thus, lineage factor requirements in cancer can switch upon challenge. The rules governing such lineage switching should be considered when designing novel lineage factor-targeted cancer therapies.
2023-07-19 | GSE183353 | GEO
Project description:Transcriptional lineage factors are a prominent class of essential genes in cancer, but the mechanisms that maintain lineage fidelity in advanced cancer clones, and whether lineage factor pathways could be broadly exploited for cancer therapy remain poorly understood. Here, we have used clear cell renal cell carcinoma (ccRCC) as a model to characterise the mechanisms that underlie lineage factor dependence in cancer. Through CRISPR/Cas9 loss-of-function screening and functional validation we find that loss of SMARCB1, a member of the SWI/SNF chromatin remodelling complex, can confer an advantage to ccRCC cells upon inhibition of the essential renal lineage factor PAX8. PAX8 inhibition resistant cells formed tumours with a dramatically altered histology showing neuroendocrine differentiation. Based on ATAC-seq and RNA-seq analysis, SMARCB1 inactivation leads to large-scale loss of kidney-specific epigenetic programmes, acquisition of a cellular state resembling that of rhabdoid tumours, and eventual activation of proliferative pathways. We show that these pathways are supported by the adoption of new transcriptional dependencies on IRF2, BHLHE40, and ZNFX1, factors that represent rare essential genes across different lineage-specific and oncogenic pathways, a principle validated in a large-scale CRISPR/Cas9 screening data set comprising hundreds of cancer cell lines. Thus, lineage factor requirements in cancer can switch upon challenge. The rules governing such lineage switching should be considered when designing novel lineage factor-targeted cancer therapies.
2023-07-19 | GSE183352 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-07-19 | GSE183354 | GEO
Project description:WNK1 enforces macrophage lineage fidelity
| PRJNA804425 | ENA
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
Project description:The SWI/SNF complex is a critical regulator of pluripotency in human embryonic stem cells (hESCs), and individual subunits have varied and specific roles during development and in diseases. The core subunit SMARCB1 is required for early embryonic survival, and mutations can give rise to atypical teratoid/rhabdoid tumors (AT/RTs) in the pediatric central nervous system. We report that in contrast to other studied systems, SMARCB1 KD relieves bivalent gene repression in hESCs and promotes chromatin accessibility at super-enhancers. Moreover, and consistent with its established role as a CNS tumor suppressor, we find that SMARCB1 is essential for neural induction but dispensable for mesodermal or endodermal differentiation. Mechanistically, we demonstrate that SMARCB1 KD cells are robustly resistant to hESC super-enhancer silencing in neural differentiation conditions. This genomic assessment of hESC chromatin regulation by SMARCB1 reveals a novel positive regulatory function at super-enhancers and a unique lineage-specific role in regulating hESC differentiation.
2019-05-14 | GSE128351 | GEO
Project description:Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.
2023-03-06 | GSE181000 | GEO
Project description:Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.
2023-03-06 | GSE180999 | GEO