Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA358712 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5128273.fastq.gz | Fastqsanger.gz | |||
| SRR5128274.fastq.gz | Fastqsanger.gz | |||
| SRR5128275.fastq.gz | Fastqsanger.gz | |||
| SRR5128276.fastq.gz | Fastqsanger.gz | |||
| SRR5128277.fastq.gz | Fastqsanger.gz |
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Project description:Chromosome loop control of oncogenic MYC produces a common vulnerability in diverse cancers
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Project description:The majority of human cancers become highly dependent on a deregulated MYC oncogene, thus identifying a common mechanism underlying MYC regulation could provide valuable targets for therapy. We show here that diverse tumor-specific super-enhancers acquired throughout the 3Mb MYC insulated neighborhood functionally interact with a single conserved site occupied by CTCF protein in the MYC promoter. CRISPR-mediated deletion analysis shows that this common CTCF site is required for super-enhancer looping to the MYC promoter, high MYC expression and rapid cell proliferation in multiple cancers. Targeted methylation of the MYC enhancer anchor by a dCAS9-DNMT3A-3L fusion protein abrogates CTCF binding with consequent loss of MYC expression, suggesting a common vulnerability and a novel approach for therapeutic targeting of aggressive cancers.
2016-12-24 | GSE92880 | GEO
Project description:The majority of human cancers become highly dependent on a deregulated MYC oncogene, thus identifying a common mechanism underlying MYC regulation could provide valuable targets for therapy. We show here that diverse tumor-specific super-enhancers acquired throughout the 3Mb MYC insulated neighborhood functionally interact with a single conserved site occupied by CTCF protein in the MYC promoter. CRISPR-mediated deletion analysis shows that this common CTCF site is required for super-enhancer looping to the MYC promoter, high MYC expression and rapid cell proliferation in multiple cancers. Targeted methylation of the MYC enhancer anchor by a dCAS9-DNMT3A-3L fusion protein abrogates CTCF binding with consequent loss of MYC expression, suggesting a common vulnerability and a novel approach for therapeutic targeting of aggressive cancers.
2018-03-20 | GSE112000 | GEO
Project description:The majority of human cancers become highly dependent on a deregulated MYC oncogene, thus identifying a common mechanism underlying MYC regulation could provide valuable targets for therapy. We show here that diverse tumor-specific super-enhancers acquired throughout the 3Mb MYC insulated neighborhood functionally interact with a single conserved site occupied by CTCF protein in the MYC promoter. CRISPR-mediated deletion analysis shows that this common CTCF site is required for super-enhancer looping to the MYC promoter, high MYC expression and rapid cell proliferation in multiple cancers. Targeted methylation of the MYC enhancer anchor by a dCAS9-DNMT3A-3L fusion protein abrogates CTCF binding with consequent loss of MYC expression, suggesting a common vulnerability and a novel approach for therapeutic targeting of aggressive cancers.
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Project description:MYC is an oncogenic driver that regulates transcriptional activation and repression, yet molecular mechanisms of MYC transformation remain unclear. We demonstrate that MYC interacts with the G9a H3K9-methyltransferase complex to control transcriptional repression. Inhibiting G9a hinders MYC chromatin binding at MYC-repressed genes and de-represses gene expression to antagonize cellular transformation. By identifying the MYC Box II region as essential for MYC-G9a interaction, a long-standing missing link between MYC transformation and gene repression is unveiled. In breast cancer, anti-proliferative sensitivity to G9a pharmacological inhibition associates with MYC sensitivity and the basal subtype. Inhibiting G9a in vivo suppresses MYC-dependent basal breast tumor growth. Our findings reveal G9a as an epigenetic regulator of MYC-mediated transcriptional repression and a therapeutic vulnerability in MYC-driven cancers.
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Project description:c-MYC (MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene, and demonstrate that BUD31 is a splicing factor required for the assembly and catalytic activity of the spliceosome. Core spliceosomal factors (SF3B1, U2AF1, and others) associate with BUD31 and are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers. Examination of intron rentention in MYC-ER HMECs, in 4 conditions
2015-09-03 | E-GEOD-66182 | biostudies-arrayexpress
Project description:MYC is a master regulator of transcriptional activation and repression that mediates diverse physiological and disease functions, including hematopoiesis, aging, and oncogenesis, yet its essential co-regulators remain unclear. We demonstrate that MYC interacts with and regulates the G9a H3K9 methyltransferase complex to control transcriptional repression in cancer. Inhibiting G9a hinders MYC binding, shifts repressive epigenetic locales to an active state, and de-represses gene expression to antagonize MYC-dependent cellular processes. MYC requires MYC Box II region for its interaction with G9a, providing a mechanism for this region essential for transcriptional repression. In treatment models of MYC-dependent basal breast cancer, genetically inhibiting G9a decreases tumour growth. Anti-proliferative sensitivity to G9a small molecule inhibitors correlates with sensitivity to MYC knockdown and associates with the basal subtype. Our findings illustrate an epigenetic model of MYC-mediated transcriptional repression in driving oncogenesis and establishes G9a as a therapeutic vulnerability in MYC-driven cancers.
2018-10-08 | GSE100335 | GEO
Project description:c-MYC (MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. Like other classic oncogenes, hyperactivation of MYC leads to collateral stresses onto cancer cells, suggesting that tumors harbor unique vulnerabilities arising from oncogenic activation of MYC. Herein, we discover the spliceosome as a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene, and demonstrate that BUD31 is a splicing factor required for the assembly and catalytic activity of the spliceosome. Core spliceosomal factors (SF3B1, U2AF1, and others) associate with BUD31 and are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total pre-mRNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Importantly, genetic or pharmacologic inhibition of the spliceosome in vivo impairs survival, tumorigenicity, and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.
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