Ets1 confers context-dependent activation of Notch signaling in T-cell leukemia
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ABSTRACT:
PROVIDER: PRJNA576685 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10259219.fastq.gz | Fastqsanger.gz | |||
| SRR10259220.fastq.gz | Fastqsanger.gz | |||
| SRR10259221.fastq.gz | Fastqsanger.gz | |||
| SRR10259222.fastq.gz | Fastqsanger.gz | |||
| SRR10259223.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Notch activation is highly prevalent in several cancers, including more than 60% of cases of T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by excessive toxicities, particularly affecting intestinal health. In order to combat Notch-driven oncogenic signals with less toxicity, one strategy is to target the transcriptional cofactors that promote tissue-specific Notch activation. We previously showed that Zmiz1 is a direct Notch1 cofactor that selectively promotes T-cell development and leukemogenic functions of Notch1. Ets1 is an excellent candidate as a transcription factor (TF) that promotes Notch functions selectively in T-ALL since the scope of Ets1 expression is far more limited than Notch expression and since Ets1 co-occupies Notch-bound enhancers with high frequency. Here, we used comparative ChIP-Seq and gene expression methods to show that Ets1 withdrawal impaired Notch complex recruitment and H3K27 acetylation at co-bound enhancers and disabled shared oncogenic pathways. ChIP-Seq showed that Ets1 peaks overlapped with 73-76% of Zmiz1 peaks and 71-75% of Notch1 peaks. Ets1 knockdown reduced Notch1, Rbpj, and Zmiz1 occupancy at enhancers that regulate genes that drive T-cell differentiation and/or T-ALL proliferation. RNA-Seq showed that Ets1 coregulated ~22% of Notch target genes with induction of Myc as a dominant and functional contribution. Our data support an emerging model in which transcription factors like Ets1 assist Notch in activating a subset of enhancers with important functions for T-cell leukemogenesis and development. Strategies that exploit the context dependence of Notch might combat the Notch pathway in cancer cells with less toxicity than pan-Notch inhibitors.
2020-07-07 | GSE138516 | GEO
Project description:Notch activation is highly prevalent in several cancers, including more than 60% of cases of T-cell acute lymphoblastic leukemia (T-ALL). However, the use of pan-Notch inhibitors to treat cancers has been hampered by excessive toxicities, particularly affecting intestinal health. In order to combat Notch-driven oncogenic signals with less toxicity, one strategy is to target the transcriptional cofactors that promote tissue-specific Notch activation. We previously showed that Zmiz1 is a direct Notch1 cofactor that selectively promotes T-cell development and leukemogenic functions of Notch1. Ets1 is an excellent candidate as a transcription factor (TF) that promotes Notch functions selectively in T-ALL since the scope of Ets1 expression is far more limited than Notch expression and since Ets1 co-occupies Notch-bound enhancers with high frequency. Here, we used comparative ChIP-Seq and gene expression methods to show that Ets1 withdrawal impaired Notch complex recruitment and H3K27 acetylation at co-bound enhancers and disabled shared oncogenic pathways. ChIP-Seq showed that Ets1 peaks overlapped with 73-76% of Zmiz1 peaks and 71-75% of Notch1 peaks. Ets1 knockdown reduced Notch1, Rbpj, and Zmiz1 occupancy at enhancers that regulate genes that drive T-cell differentiation and/or T-ALL proliferation. RNA-Seq showed that Ets1 coregulated ~22% of Notch target genes with induction of Myc as a dominant and functional contribution. Our data support an emerging model in which transcription factors like Ets1 assist Notch in activating a subset of enhancers with important functions for T-cell leukemogenesis and development. Strategies that exploit the context dependence of Notch might combat the Notch pathway in cancer cells with less toxicity than pan-Notch inhibitors.
2020-07-07 | GSE138659 | GEO
Project description:Ets1 confers context-dependent activation of Notch signaling in T-cell leukemia [ChIP-Seq]
| PRJNA576230 | ENA
Project description:Ets1 confers context-dependent activation of Notch signaling in T-cell leukemia [RNA-Seq]
| PRJNA576692 | ENA
Project description:Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL). But in clinical trials, pan-Notch inhibitors caused excessive toxicity. To find alternative ways to target Notch signals, we investigated Cell division cycle 73 (Cdc73), which is a component of the RNA polymerase-associated transcriptional machinery and has been previously described as a Notch cofactor. Emerging evidence also suggests that transcriptional machinery might be an attractive vulnerability in T-ALL. In this setting, we show that CDC73 co-binds a subset of Notch-occupied regulatory elements in an ETS1-dependent context. In mouse models, Cdc73 is important for Notch-induced T-cell development and maintenance of Notch-induced T-ALL. Mechanistically, Cdc73, Ets1, and Notch activate genes that promote DNA repair and oxidative phosphorylation. Cdc73 induces these pathways through canonical functions in mRNA synthesis rather than non-canonical functions in enhancer activation. Our study suggests that Cdc73 acts through context-dependent mechanisms to promote a gene expression program that mitigates the genotoxic and metabolic stress of supraphysiological Notch signaling. We also provide mechanistic support for testing inhibitors of DNA repair, oxidative phosphorylation, and transcriptional machinery as anti-leukemic therapy while highlighting strategies that disable pathways that intersect with Notch at chromatin to target Notch signals without directly targeting the Notch complex.
2023-08-30 | GSE221339 | GEO
Project description:Activated Notch signaling is highly prevalent in T-cell acute lymphoblastic leukemia (T-ALL). But in clinical trials, pan-Notch inhibitors caused excessive toxicity. To find alternative ways to target Notch signals, we investigated Cell division cycle 73 (Cdc73), which is a component of the RNA polymerase-associated transcriptional machinery and has been previously described as a Notch cofactor. Emerging evidence also suggests that transcriptional machinery might be an attractive vulnerability in T-ALL. In this setting, we show that CDC73 co-binds a subset of Notch-occupied regulatory elements in an ETS1-dependent context. In mouse models, Cdc73 is important for Notch-induced T-cell development and maintenance of Notch-induced T-ALL. Mechanistically, Cdc73, Ets1, and Notch activate genes that promote DNA repair and oxidative phosphorylation. Cdc73 induces these pathways through canonical functions in mRNA synthesis rather than non-canonical functions in enhancer activation. Our study suggests that Cdc73 acts through context-dependent mechanisms to promote a gene expression program that mitigates the genotoxic and metabolic stress of supraphysiological Notch signaling. We also provide mechanistic support for testing inhibitors of DNA repair, oxidative phosphorylation, and transcriptional machinery as anti-leukemic therapy while highlighting strategies that disable pathways that intersect with Notch at chromatin to target Notch signals without directly targeting the Notch complex.
2023-08-30 | GSE219097 | GEO
Project description:Overexpression of the oncogene MEF2C oposses NOTCH signalling in T versus B lineage decision, driving leukemia in the thymus context
2022-05-14 | GSE159506 | GEO
Project description:Overexpression of the oncogene MEF2C opposes NOTCH signalling in T versus B lineage decision, driving leukemia in the thymus context
2022-05-14 | GSE160407 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-07-07 | GSE138660 | GEO
Project description:Notch signaling regulates a variety of developmental cell fates decisions in a cell-context dependent manner. Although Notch signaling directly regulates transcription via the RBP-J/CSL DNA binding protein, little is known about the genes in the respective tissues that are directly activated by Notch. To analyze how Notch signaling mediates its context dependent functions, we utilized a Tamoxifen(OHT)-inducible system (NERT) to activate Notch1 in embryonic stem cells (ESC) at different stages of mesodermal differentiation combined with global transcriptional analyses. Notch1 signaling pathway was analysed in mouse embryonic stem cells (mESCs) that were kept under self-renewal conditions enabling ectodermal, or mesodermal gene expression (ESCe or ESCm respectively), or were differentiated into mesodermal progenitors. NotchIC were induced or not induced by hydroxytamoxifen (OHT) and addititionally in some experiments the cells were treated with protein synthesis inhibitor cycloheximide (CHX) for 4 h.
2010-07-13 | E-GEOD-15268 | biostudies-arrayexpress