Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA326874 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3720820_1.fastq.gz | Fastqsanger.gz | |||
| SRR3720820_2.fastq.gz | Fastqsanger.gz | |||
| SRR3720830.fastq.gz | Fastqsanger.gz | |||
| SRR3720821_1.fastq.gz | Fastqsanger.gz | |||
| SRR3720821_2.fastq.gz | Fastqsanger.gz |
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Project description:PAX3-FOXO1 establishes myogenic super enhancers [RMS Chip-seq]
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Project description:The fusion transcription factor PAX3-FOXO1 drives oncogenesis in a subset of rhabdomyosarcomas, however the mechanisms by which it remodels chromatin are unknown. We find PAX3-FOXO1 reprograms the cis-regulatory landscape by inducing super enhancers (SEs), in collaboration with master transcription factors MYOG, MYOD and MYCN. This myogenic SE circuitry is consistent across cell lines and primary tumors. Deregulation of PAX3-FOXO1 itself occurs by translocation-induced chromatin loops bringing the PAX3 promoter under the control of FOXO1 enhancers. Protein targets induced by, or bound to, PAX3-FOXO1 occupied SEs, were selectively sensitive to small molecule inhibition. PAX3-FOXO1 co-binds BRD4 at SEs, and BET bromodomains are required for PAX3-FOXO1-dependent transcription and cancer cell growth.
2017-04-27 | GSE83726 | GEO
Project description:The fusion transcription factor PAX3-FOXO1 drives oncogenesis in a subset of rhabdomyosarcomas, however the mechanisms by which it remodels chromatin are unknown. We find PAX3-FOXO1 reprograms the cis-regulatory landscape by inducing super enhancers (SEs), in collaboration with master transcription factors MYOG, MYOD and MYCN. This myogenic SE circuitry is consistent across cell lines and primary tumors. Deregulation of PAX3-FOXO1 itself occurs by translocation-induced chromatin loops bringing the PAX3 promoter under the control of FOXO1 enhancers. Protein targets induced by, or bound to, PAX3-FOXO1 occupied SEs, were selectively sensitive to small molecule inhibition. PAX3-FOXO1 co-binds BRD4 at SEs, and BET bromodomains are required for PAX3-FOXO1-dependent transcription and cancer cell growth.
2017-04-27 | GSE83725 | GEO
Project description:The fusion transcription factor PAX3-FOXO1 drives oncogenesis in a subset of rhabdomyosarcomas, however the mechanisms by which it remodels chromatin are unknown. We find PAX3-FOXO1 reprograms the cis-regulatory landscape by inducing super enhancers (SEs), in collaboration with master transcription factors MYOG, MYOD and MYCN. This myogenic SE circuitry is consistent across cell lines and primary tumors. Deregulation of PAX3-FOXO1 itself occurs by translocation-induced chromatin loops bringing the PAX3 promoter under the control of FOXO1 enhancers. Protein targets induced by, or bound to, PAX3-FOXO1 occupied SEs, were selectively sensitive to small molecule inhibition. PAX3-FOXO1 co-binds BRD4 at SEs, and BET bromodomains are required for PAX3-FOXO1-dependent transcription and cancer cell growth.
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Project description:Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by a translocation that creates the chimeric transcription factor PAX3-FOXO1 (P3F), which assembles de novo super enhancers to drive high levels of transcription of other core regulatory transcription factors (CRTFs). P3F recruits co-regulatory factors to super enhancers such as BRD4, which recognizes acetylated lysines via BET bromodomains. In this study, we demonstrate that inhibition or degradation of BRD4 leads to global decreases in transcription, and selective downregulation of CRTFs. We also show that the BRD4 degrader ARV-771 halts transcription while preserving RNA Polymerase II (Pol2) loops between super enhancers and their target genes, and causes the removal of Pol2 only past the transcriptional end site of CRTF genes, suggesting a novel effect of BRD4 on Pol2 looping. We finally test the most potent molecule, inhibitor BMS-986158, in an orthotopic PDX mouse model of FP-RMS with additional high-risk mutations, and find that it is well tolerated in vivo and leads to an average decrease in tumor size. This effort represents a partnership with an FP-RMS patient and family advocates to make preclinical data rapidly accessible to the family, and to generate data to inform future patients who develop this disease.
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Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.
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Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma is an aggressive childhood soft tissue sarcoma, mainly driven by the pathognomonic PAX3–FOXO1, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability to the PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth, disrupting the expression of CRC TFs in accordance with the alterations of PAX3–FOXO1-determining super enhancers. Combination of KDM4B inhibitor with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable epigenetic modifier required for the functions of PAX3–FOXO1, which may translate to a novel therapeutic approach for the high-risk RMS.
2022-09-06 | GSE157093 | GEO
Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.
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Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.
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Project description:Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic PAX3–FOXO1 fusion protein, which governs a core regulatory circuitry transcription factor (CRC TF) network. Here we show that the histone lysine demethylase KDM4B is a therapeutic vulnerability for PAX3–FOXO1+ RMS. Genetic and pharmacologic inhibition of KDM4B significantly delays tumor growth by disrupting the expression of CRC TFs caused by epigenetic alterations of PAX3–FOXO1-governed super enhancers. Combining KDM4B inhibition with cytotoxic chemotherapy leads to significant tumor regression in preclinical PAX3–FOXO1+ RMS models. In summary, we have identified a targetable mechanism required for maintenance of PAX3-FOXO1-related CRC TF network, which may translate to a novel therapeutic approach for fusion-positive RMS.
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