Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-62500
PROVIDER: PRJNA229995 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1616140.fastq.gz | Fastqsanger.gz | |||
| SRR1616141.fastq.gz | Fastqsanger.gz | |||
| SRR1616142.fastq.gz | Fastqsanger.gz | |||
| SRR1616137.fastq.gz | Fastqsanger.gz | |||
| SRR1616138.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 6 |
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Project description:PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies [ChIP-seq]
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Project description:PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies [expression array]
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Project description:The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types1. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer2,3. Here we provide genomic, cellular, and mouse mod- elling data demonstrating that the polycomb group gene SUZ12 func- tions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras4. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhib- itors. Collectively, these studies not only reveal an unexpected con- nection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers. 2x3 samples (DMSO and PDJQ treated; WCL, BRD4 and H3K27Ac pulldown)
2014-10-21 | E-GEOD-62499 | biostudies-arrayexpress
Project description:The polycomb repressive complex 2 (PRC2) plays an oncogenic role in several cancers. However, loss-of-function mutations in PRC2 components have been detected in a subset of hematopoietic malignancies, suggesting that different epigenetic landscapes are required in different tumor types. In this study we provide genomic, cellular, and mouse modeling data to demonstrate that loss-of-function mutations in the polycomb gene, SUZ12, and NF1 cooperate in peripheral nervous system tumors, glioblastomas, and melanomas. NF1 encodes a Ras GTPase-activating protein and its loss triggers moderate levels of Ras activation. We show that SUZ12-loss enhances the effects of NF1 mutations, in part, by amplifying Ras transcriptional signatures. Moreover, SUZ12-loss triggers an epigenetic switch that confers sensitivity to combined bromodomain and MEK inhibitors in vivo. Collectively these studies demonstrate an unexpected role for polycomb group genes in NF1 mutant tumors and reveal an epigenetic-based therapeutic strategy that may be exploited for a variety of cancers. 9 samples in triplicates, 3x LacZ control, 3x SUZ12 over expression, 3x JQ1 treatment
2014-07-01 | E-GEOD-52777 | biostudies-arrayexpress
Project description:SUZ12 and NF1 loss cooperate to enhance Ras transcriptional output and sensitize cancers to epigenetic therapies
2025-01-24 | E-GEOD-52777 | ExpressionAtlas
Project description:The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types1. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, sug- gesting that this complex plays a dichotomous and poorly understood role in cancer2,3. Here we provide genomic, cellular, and mouse mod- elling data demonstrating that the polycomb group gene SUZ12 func- tions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras4. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhib- itors. Collectively, these studies not only reveal an unexpected con- nection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers. 9 samples in triplicates, 3x LacZ control, 3x SUZ12 over expression, 3x JQ1 treatment
2014-10-21 | E-GEOD-62500 | biostudies-arrayexpress
Project description:The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types1. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer2,3. Here we provide genomic, cellular, and mouse mod- elling data demonstrating that the polycomb group gene SUZ12 func- tions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras4. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhib- itors. Collectively, these studies not only reveal an unexpected con- nection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.
2014-10-21 | GSE62499 | GEO
Project description:The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types1. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, sug- gesting that this complex plays a dichotomous and poorly understood role in cancer2,3. Here we provide genomic, cellular, and mouse mod- elling data demonstrating that the polycomb group gene SUZ12 func- tions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras4. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhib- itors. Collectively, these studies not only reveal an unexpected con- nection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.
2014-10-21 | GSE62500 | GEO
Project description:Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukemia (AML), BET inhibitors are being explored as promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced hematologic malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukemia, we performed a chromatin-focused shRNAmir screen in a sensitive MLL/AF9; NrasG12D‑driven AML model, and investigated dynamic transcriptional profiles in sensitive and resistant murine and human leukemias. Our screen reveals that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodeling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukemias regardless of their sensitivity, resistant leukemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signaling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic ChIP- and STARR-seq enhancer profiles reveal that BET-resistant states are characterized by remodeled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signaling as a driver and candidate biomarker of primary and acquired BET resistance in leukemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies. RNA-Seq of DMSO- or JQ1-treated cancer cell lines; ChIP-seq for H3K36me3 and H3K27me3 in a leukemia cell line treated either with DMSO or JQ1, ChIP-seq for H3K27ac in resistant and sensitive mouse and human leukemia. Functional enhancer mapping (STARR-seq) in K-562 treated either with DMSO or JQ1.
2015-09-08 | E-GEOD-63782 | biostudies-arrayexpress
Project description:BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration resistant prostate cancer (CRPC) cells. Bromodomain and extraterminal protein (BET) inhibitors displace BRD4 protein from chromatin, resulting in the inhibition of oncogenic transcriptional programs. Several BET inhibitors (BETi) are currently being evaluated in clinical trials for a variety of malignancies, including CRPC. Here we describe a general mechanism of acquired resistance to BETi due to modulation of cellular pathways that are amenable to targeted therapies in CRPC cells. BETi resistant CRPC cells displayed cross resistance to a variety of BETi in the absence of gatekeeper mutations or persistent drug pump activation. Resistant cells exhibited reduced chromatin bound BRD4, and were less sensitive to Proteolysis Targeting Chimeric (PROTAC) -mediated degradation or genetic knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR-signaling due to CDK9-mediated serine-81 phosphorylation of AR, with a consequent increase in sensitivity to CDK9 inhibitors and enzalutamide in BETi resistant cells. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DNA damage response (DDR) genes was observed due to the loss of BRD4 from their proximal promoter regions in the resistant cells, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy in CRPC. However, data showing the reactivation of AR-signaling and increased DNA damage in the BETi resistant cells provide unique opportunities for combination therapies in managing CRPC.
2018-02-27 | GSE103082 | GEO