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| Status |
Public on Jul 07, 2020 |
| Title |
Ets1 confers context-dependent activation of Notch signaling in T-cell leukemia [ChIP-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
ChIP-Seq analysis of THP-6 cells, a human T-ALL cell line, that was transduced with shControl and two independent shEts1. ChIP-quality antibodies target Ets1 (sc, cleaved Notch1 (ICN1), Rbpj, Zmiz1, and H3K27ac.
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| Contributor(s) |
McCarter A, Saari T, Chiang M, Russell R |
| Citation(s) |
32924017 |
| |
| Submission date |
Oct 07, 2019 |
| Last update date |
Feb 08, 2021 |
| Contact name |
Mark Yat-fung Chiang |
| E-mail(s) |
[email protected]
|
| Organization name |
University of Michigan
|
| Department |
Internal Medicine/Heme-onc
|
| Lab |
Room 2838
|
| Street address |
109 Zina Pitcher Place
|
| City |
Ann Arbor |
| State/province |
MI |
| ZIP/Postal code |
48019-2200 |
| Country |
USA |
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| Platforms (1) |
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| Samples (31)
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| This SubSeries is part of SuperSeries: |
| GSE138660 |
Ets1 confers context-dependent activation of Notch signaling in T-cell leukemia |
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| Relations |
| BioProject |
PRJNA576230 |
| SRA |
SRP224631 |
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