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Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma [RNA-seq]

ABSTRACT: Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma [RNA-seq]

PROVIDER: PRJNA532233 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8879090.fastq.gz	Fastqsanger.gz
	SRR8879100.fastq.gz	Fastqsanger.gz
	SRR8879091.fastq.gz	Fastqsanger.gz
	SRR8879101.fastq.gz	Fastqsanger.gz
	SRR8879092.fastq.gz	Fastqsanger.gz

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Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma [RNA-seq]

Project description:We have used a mouse model where melanoma can be induced by Tamoxifen treatment that induces expression of oncogenic Braf and deletion of Pten in the melanocyte lineage using a Tyr::Cre-ER-T2 transgene to mediate recombination. Cells from these melanoma tumours were cultured in vitro and the effects of siRNA mediated silencing of transcription factors Mitf and Sox10 was performed and analysed by RNA-seq. We then crossed these mice with mice bearing floxed alleles of the genes encoding the chromatin remodelling factors Bptf and Brg1 (Smarca4). Tumour cells were grown in culture and Bptf or Brg1 inactivated by 4-OHT treatment. The effects on gene expression were assessed by RNA-seq.

2019-04-17 | GSE129620 | GEO

Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma [ChIP-seq]

Project description:Somatic oncogenic mutation of BRAF coupled with inactivation of PTEN constitute a frequent combination of genomic alterations driving development of human melanoma. Mice genetically engineered to conditionally express oncogenic BrafV600E and inactivate Pten in melanocytes following tamoxifen treatment rapidly develop melanoma. While early stage melanomas comprised melanin-pigmented Mitf and Dct-expressing cells, expression of these and other melanocyte identity genes was lost in later stage tumours that showed histological and molecular characteristics of de-differentiated neural crest type cells. Melanocyte identity genes displayed loss of active chromatin marks and RNA polymerase II and gain of heterochromatin marks indicating epigenetic reprogramming during tumour progression. Nevertheless, late stage tumour cells grown in culture re-expressed Mitf and melanocyte markers and Mitf together with Sox10 co-regulated a large number of genes essential for their growth. In this melanoma model, somatic inactivation that the catalytic Brg1 (Smarca4) subunit of the SWI/SNF complex and the scaffolding Bptf subunit of the NuRF delayed tumour formation and deregulated large and overlapping gene expression programs essential for normal tumour cell growth. Moreover, we show that Brg1 and Bptf co-regulated many genes together with Mitf and Sox10. Together these transcription factors and chromatin remodelling complexes orchestrate essential gene expression programs in mouse melanoma cells

2019-04-17 | GSE100998 | GEO

Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma

Project description:Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma

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The role of BPTF in melanoma progression and in response to BRAF-targeted therapy

Project description:These studies demonstrate multiple pro-tumorigenic functions for BPTF, and identify it as a novel target for anti-cancer therapy. They also suggest the combination of BPTF targeting with BRAF inhibitors as a novel therapeutic strategy for melanomas with mutant BRAF.

2015-03-05 | GSE64152 | GEO

Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma.

Project description:Somatic oncogenic mutation of BRAF coupled with inactivation of PTEN constitute a frequent combination of genomic alterations driving the development of human melanoma. Mice genetically engineered to conditionally express oncogenic BrafV600E and inactivate Pten in melanocytes following tamoxifen treatment rapidly develop melanoma. While early-stage melanomas comprised melanin-pigmented Mitf and Dct-expressing cells, expression of these and other melanocyte identity genes was lost in later stage tumours that showed histological and molecular characteristics of de-differentiated neural crest type cells. Melanocyte identity genes displayed loss of active chromatin marks and RNA polymerase II and gain of heterochromatin marks, indicating epigenetic reprogramming during tumour progression. Nevertheless, late-stage tumour cells grown in culture re-expressed Mitf, and melanocyte markers and Mitf together with Sox10 coregulated a large number of genes essential for their growth. In this melanoma model, somatic inactivation that the catalytic Brg1 (Smarca4) subunit of the SWI/SNF complex and the scaffolding Bptf subunit of the NuRF complex delayed tumour formation and deregulated large and overlapping gene expression programs essential for normal tumour cell growth. Moreover, we show that Brg1 and Bptf coregulated many genes together with Mitf and Sox10. Together these transcription factors and chromatin remodelling complexes orchestrate essential gene expression programs in mouse melanoma cells.

| S-EPMC7205870 | biostudies-literature

Genome-wide occupancy of chromatin remodeller SMARCAL1 and BRG1 in human cells

Project description:In this study we report genome wide occupancy of SMARCAL1 and BRG1 in control HeLa cells. Our analysis showed binding of these two remodellers on DNA damage response gene, chromatin remodellers, cell cycle and apoptosis regulating genes.

2019-09-12 | GSE137250 | GEO

Fusion partners influence cellular and molecular phenotypes of oncogenic BRAF fusions

Project description:Fusion genes can be oncogenic drivers in a variety of cancer types and represent potential targets for targeted therapy. The BRAF gene is frequently involved in oncogenic fusions, with fusion frequencies of 0.2-3% throughout different cancers. However, BRAF fusions rarely occur in the same gene configuration, potentially challenging personalized therapy design. In particular, the influence that is imposed by the wide variety of fusion partners on the oncogenic role of BRAF during tumor growth and drug response is unknown. Here, we used patient-derived colorectal cancer organoids to functionally characterize and cross-compare previously identified BRAF fusions containing various partner genes (AGAP3, DLG1 and TRIM24) with respect to cellular behaviour, downstream signaling activation and response to targeted therapies. We demonstrate that 5’ partner choice of BRAF fusions affects their subcellular localization and intracellular signaling capacity. In particular the DLG1-BRAF fusion protein showed distinct localization to the plasma membrane and exhibited increased activation of downstream MAPK signaling under unperturbed conditions. Moreover, phosphoproteomics and RNA sequencing identified distinct subsets of affected signaling pathways and altered gene expression of BRAF fusions. The different BRAF fusions exhibited varying sensitivities to simultaneous targeted inhibition of MEK and the EGF receptor family. However, all BRAF fusions conveyed resistance to targeted monotherapy against the EGF receptor family, suggesting that BRAF fusions should be screened alongside other MAPK pathway alterations to identify mCRC patients to exclude from cetuximab treatment

2020-01-16 | PXD013461 | Pride

Degree of Tissue Differentiation Dictates Susceptibility to BRAF-driven Colorectal Cancer

Project description:In murine models, we find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation and senescence. This corresponds to inefficient tumor formation in oncogenic BRAF mouse models of colon cancer. By reducing levels of differentiation in the gut via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2), stem cell activity is restored in BRAFV600E intestines, and the oncogenic capacity of mutant BRAF is amplified. In human patients, we observe that reduced levels of differentiation in normal tissue is associated with increased susceptibility to serrated colon tumors. Together, these findings help resolve the conditions necessary for BRAF-driven colon cancer initiation.

2017-12-26 | GSE106330 | GEO

Mus musculus

Project description:Chromatin remodellers Brg1 and Bptf are required for normal gene expression and progression of oncogenic Braf-driven mouse melanoma [ChIP-seq]

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Signaling and transcriptional dynamics underlying early adaptation to oncogenic BRAF inhibition

Project description:A major contributor to poor sensitivity to anti-cancer kinase inhibitor therapy is drug-induced cellular adaptation, whereby remodeling of signaling and gene regulatory networks permits a drug-tolerant phenotype. Here, we resolve the scale and kinetics of critical subcellular events following oncogenic kinase inhibition and preceding cell cycle re-entry, using mass spectrometry-based phosphoproteomics and RNA sequencing to capture molecular snapshots within the first minutes, hours, and days of BRAF kinase inhibitor exposure in a human BRAF-mutant melanoma model of adaptive therapy resistance. By enriching specific phospho-motifs associated with mitogenic kinase activity, we monitored the dynamics of thousands of growth- and survival-related protein phosphorylation events under oncogenic BRAF inhibition and drug removal. We observed early and sustained inhibition of the BRAF-ERK axis, gradual downregulation of canonical cell cycle-dependent signals, and three distinct and reversible phase transitions toward quiescence. Statistical inference of kinetically-defined regulatory modules revealed a concerted response to oncogenic BRAF inhibition and a dominant compensatory induction of SRC family kinase (SFK) signaling, which we found to be at least partially driven by accumulation of reactive oxygen species via impaired redox homeostasis. This induction sensitized cells to co-treatment with an SFK inhibitor across a panel of patient-derived melanoma cell lines and in an orthotopic mouse xenograft model, underscoring the translational potential for measuring the temporal dynamics of signaling and transcriptional networks under therapeutic challenge.

2024-02-27 | PXD048479 | Pride

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