Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA374534 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5249476_1.fastq.gz | Fastqsanger.gz | |||
| SRR5249476_2.fastq.gz | Fastqsanger.gz | |||
| SRR5249477_1.fastq.gz | Fastqsanger.gz | |||
| SRR5249477_2.fastq.gz | Fastqsanger.gz |
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Project description:Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma
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Project description:Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma [array]
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Project description:Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma [ChIP-Seq]
| PRJNA374532 | ENA
Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
2023-05-10 | PXD039332 | Pride
Project description:Neuroblastoma is a pediatric tumor that accounts for more than 15% of cancer-related deaths in children. Survival chances for high-risk patients are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumors respond to retinoic acid-mediated differentiation. Among neuroblastoma tumors, two phenotypically distinct cell types-adrenergic (ADRN) and mesenchymal (MES), have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries. We hypothesized that distinct super-enhancers in these different tumor cells could mediate differential response to retinoic acid. To this end, we treated four different neuroblastoma cell lines, comprising both ADRN (MYCN amplified and non-amplified) and MES subtypes, with retinoic acid and studied the super-enhancer landscape upon treatment and after removal of retinoic acid. Using H3K27ac ChIP-seq paired with RNA-seq, we compared the super-enhancers in cells that respond to retinoic acid-mediated differentiation versus those that fail to differentiate. We identified unique super-enhancers associated with cells differentiation; however, even among cells that respond to treatment, there was heterogeneity upon removal of retinoic acid, with MYCN amplified cells remaining differentiated whereas MYCN non-amplified cells reverted to a proliferative state. This study identifies regulatory super-enhancers as a plausible mechanism behind the differential response to retinoic acid-mediated differentiation.
2022-07-28 | GSE202239 | GEO
Project description:Neuroblastoma is a pediatric tumor that accounts for more than 15% of cancer-related deaths in children. Survival chances for high-risk patients are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumors respond to retinoic acid-mediated differentiation. Among neuroblastoma tumors, two phenotypically distinct cell types-adrenergic (ADRN) and mesenchymal (MES), have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries. We hypothesized that distinct super-enhancers in these different tumor cells could mediate differential response to retinoic acid. To this end, we treated four different neuroblastoma cell lines, comprising both ADRN (MYCN amplified and non-amplified) and MES subtypes, with retinoic acid and studied the super-enhancer landscape upon treatment and after removal of retinoic acid. Using H3K27ac ChIP-seq paired with RNA-seq, we compared the super-enhancers in cells that respond to retinoic acid-mediated differentiation versus those that fail to differentiate. We identified unique super-enhancers associated with cells differentiation; however, even among cells that respond to treatment, there was heterogeneity upon removal of retinoic acid, with MYCN amplified cells remaining differentiated whereas MYCN non-amplified cells reverted to a proliferative state. This study identifies regulatory super-enhancers as a plausible mechanism behind the differential response to retinoic acid-mediated differentiation.
2022-07-28 | GSE201179 | GEO
Project description:Half of the children diagnosed with neuroblastoma have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from neuroblastoma tissues are lacking. Here, using genome-wide H3K27ac profiles across 60 neuroblastomas, covering the different clinical and molecular subtypes, we identified four major super enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups, namely MYCN amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk neuroblastomas. The fourth subtype, exhibiting mesenchymal characteristics, shared features with multipotent Schwann cell precursors, was induced by RAS activation and enriched in relapsed disease. Notably, CCND1, a disease essential gene, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Together, this reveals subtype-specific super-enhancer regulation in neuroblastoma.
| EGAS00001004552 | EGA
Project description:Half of the children diagnosed with neuroblastoma have high-risk disease, disproportionately contributing to overall childhood cancer-related deaths. In addition to recurrent gene mutations, there is increasing evidence supporting the role of epigenetic deregulation in disease pathogenesis. Yet, comprehensive cis-regulatory network descriptions from neuroblastoma tissues are lacking. Here, using genome-wide H3K27ac profiles across 60 neuroblastomas, covering the different clinical and molecular subtypes, we identified four major super enhancer-driven epigenetic subtypes and their underlying master regulatory networks. Three of these subtypes recapitulated known clinical groups, namely MYCN amplified, MYCN non-amplified high-risk and MYCN non-amplified low-risk neuroblastomas. The fourth subtype, exhibiting mesenchymal characteristics, shared features with multipotent Schwann cell precursors, was induced by RAS activation and enriched in relapsed disease. Notably, CCND1, a disease essential gene, was regulated by both mesenchymal and adrenergic regulatory networks converging on distinct super-enhancer modules. Together, this reveals subtype-specific super-enhancer regulation in neuroblastoma.
| EGAS00001004551 | EGA
Project description:Bromodomain-containing protein 4 (BRD4) functions as an epigenetic reader and binds to so-called super-enhancer regions of driving oncogenes such as MYC in cancer. We investigated the possibility to target super-enhancer regulated genes in neuroblastoma and in MYCN amplified disease in particular. We used OTX015, the first small-molecule BRD4 inhibitor to enter clinical phase I/II trials in adults, to test the feasibility to specifically target super-enhancer regulated gene-expression in neuroblastoma. BRD4 inhibition lead to significant transcriptional down-regulation of genes that were associated with super-enhancers, supporting the notion that BRD4 preferentially acts at these chromatin sites. BRD4 inhibition not only attenuated MYCN transcription but most significantly affected MYCN-regulated transcriptional programs.
2016-07-03 | E-MTAB-3672 | biostudies-arrayexpress
Project description:A small set of core transcription factors (TFs) dominates control of the gene expression program in embryonic stem cells and other well-studied cellular models. These core TFs collectively regulate their own gene expression, thus forming an interconnected autoregulatory loop that can be considered the core transcriptional regulatory circuitry (CRC) for that cell type. There is limited knowledge of core TFs, and thus models of core regulatory circuitry, for most cell types. We recently discovered that genes encoding known core TFs forming CRCs are driven by super-enhancers, which provides an opportunity to systematically predict CRCs in poorly studied cell types through super-enhancer mapping. Here we use super-enhancer maps to generate CRC models for 75 human cell and tissue types. These core circuitry models should prove valuable for further investigating cell type-specific transcriptional regulation in healthy and diseased cells. ChIP-Seq for RUNX1 and GATA3 in Jurkat T cell acute lymphoblastic leukemia cells.
2015-12-18 | E-GEOD-76181 | biostudies-arrayexpress