BPTF cooperates with MYCN/MYC to link neuroblastoma cell cycle control with epigenetic cell states
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ABSTRACT:
PROVIDER: PRJNA1079811 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28074729.fastq.gz | Fastqsanger.gz | |||
| SRR28074730.fastq.gz | Fastqsanger.gz | |||
| SRR28074731.fastq.gz | Fastqsanger.gz | |||
| SRR28074732.fastq.gz | Fastqsanger.gz | |||
| SRR28074733.fastq.gz | Fastqsanger.gz |
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Project description:The nucleosome remodeling factor BPTF is required for the deployment of the MYC-driven transcriptional program. Deletion of oneBptfallele delays tumor progression in mouse models of pancreatic cancer and lymphoma. In neuroblastoma, MYCN cooperates with the transcriptional core regulatory circuitry (CRC). HighBPTFlevels are associated with high-risk features and decreased survival. BPTFdepletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation ofBPTFand CRCtranscription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role forBPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes withthe CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target.
2025-02-23 | GSE256511 | GEO
Project description:The nucleosome remodeling factor BPTF is required for the deployment of the MYC-driven transcriptional program. Deletion of oneBptfallele delays tumor progression in mouse models of pancreatic cancer and lymphoma. In neuroblastoma, MYCN cooperates with the transcriptional core regulatory circuitry (CRC). HighBPTFlevels are associated with high-risk features and decreased survival. BPTFdepletion results in a dramatic decrease of cell proliferation. Bulk RNA-seq, single-cell sequencing, and tissue microarrays reveal a positive correlation ofBPTFand CRCtranscription factor expression. Immunoprecipitation/mass spectrometry shows that BPTF interacts with MYCN and the CRC. Genome-wide distribution analysis of BPTF and CRC in neuroblastoma reveals a dual role forBPTF: 1) it co-localizes with MYCN/MYC at the promoter of genes involved in cell cycle and 2) it co-localizes withthe CRC at super-enhancers to regulate cell identity. The critical role of BPTF across neuroblastoma subtypes supports its relevance as a therapeutic target.
2025-02-26 | GSE259246 | GEO
Project description:BPTF cooperates with MYCN/MYC to link neuroblastoma cell cycle control with epigenetic cell states [Cut&Run]
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Project description:To evaluate the expression of genes associated with MYCN in NB, 10 tumors with MYCN amplification and 10 with normal MYCN copy number were subjected to oligonucleotide microarray using Agilent oligo microarray chips. Two-condition experiment, MYCN normal vs. MYCN amplified 10 NB patient tissues for each group.
2013-12-17 | E-GEOD-53371 | biostudies-arrayexpress
Project description:Here we sought metabolic alterations specifically associated with amplified MYCN as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified 7 proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these were phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing 13C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NMRI-Foxn1nu/nu mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHDGH knockout and inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach must be considered with caution in patients with neuroblastoma.
2020-12-11 | PXD018300 | Pride
Project description:To evaluate the expression of genes associated with MYCN in NB, 10 tumors with MYCN amplification and 10 with normal MYCN copy number were subjected to oligonucleotide microarray using Agilent oligo microarray chips.
2013-12-17 | GSE53371 | GEO
Project description:MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) that predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to aggressiveness in MNA+ NB remains poorly understood. Here we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently co-expressed with MYCN, and promotes cell survival in MNA+ NB. GREB1 controls gene expression independently of MYCN in MNA+ NB, among which we uncover Myosin 1B (MYO1B) as being highly expressed in MNA+ NB. MYO1B promotes aggressive features, including invasive capacity in vitro, as well as extravasation and distant metastasis in vivo. Global secretome and proteome profiling further delineate MYO1B as a major regulator of secretome reprogramming in MNA+ NB cells. Moreover, we identify the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism that promotes the aggressiveness of MNA+ NB, and independently of MYCN. Furthermore, we find that MYO1B is upregulated in association with other oncoproteins during cellular transformation, and is dramatically increased in multiple human cancer types, suggesting a crucial role of MYO1B in cancers in addition to MNA+ NB.
2023-10-24 | PXD039410 | Pride
Project description:The MYCN locus is amplified in about half of high-risk neuroblastoma tumors. To identify genomic loci occupied by MYCN protein in the MYCN-amplified neuroblastoma cell lines NGP, Kelly and NB-1643, we performed chromatin immunoprecipitation coupled with Next-Generation Sequencing (ChIP-seq) using an anti-MYCN antibody.
2017-08-02 | GSE94782 | GEO
Project description:Inducible MYCN-knockdown, followed by RNA-seq analysis in the MYCN-amplified neuroblastoma cell line IMR5-75, reveals profound time-dependent transcriptome changes. For modulation of MYCN levels, stable neuroblastoma cell models were used where MYCN can be downregulated via vector-based hairpin RNA induction upon addition of 1µg/ml tetracycline (IMR5-75-shMYCN. From cells treated either with tetracycline or solvent (ethanol), RNA was isolated at time points 6 hours, 12 hours and 24 hours. Experiments were done in duplicates. RNA was sequenced.
2016-09-08 | E-GEOD-80397 | biostudies-arrayexpress
Project description:High risk - neuroblastoma (HR-NB) is a pediatric solid tumor with high lethality. Half of HR-NB are driven by MYCN gene amplification (MNA). These HR-NBs require high dosage chemotherapy and often relapse. Moreover, current therapies can cause severe long-term side effects and new therapies are urgently needed. This study investigates a novel therapeutic approach targeting the metabolic vulnerabilities of MNA NB cells. We discovered that Diphenyleneiodonium chloride (DPI), an inhibitor 2 of flavoprotein enzymes and mitochondrial complex I, synergizes with mitoquinone mesylate (MitoQ), a mitochondria-targeted antioxidant in 2D and 3D in vitro models of NB. Similarly to DPI, MitoQ appears to have a greater effect on cells with higher MYCN levels. Furthermore, low nanomolar concentrations of MitoQ significantly decrease MYCN protein expression and induce differentiation of MNA cells. The DPI and MitoQ combination further synergizes with vincristine, a chemotherapeutic agent used in NB treatment. Phosphoproteomics and proteomics analysis suggests that the drug combination induces MNA NB cell death by arresting the cell cycle and inhibiting oxidative phosphorylation (OXPHOS) in the mitochondria. Thus, interference with mitochondrial metabolism may represent an effective strategy to enhance the activity of chemotherapeutic drugs in MNA-NB.
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