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| Status |
Public on Nov 09, 2021 |
| Title |
EP300 selectively controls the enhancer landscape of MYCN-amplified neuroblastoma [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Gene expression is regulated by promoters and enhancers marked by histone H3-lysine-27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HATs), EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastomas (NB) depend on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2?, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeted-chimaera (PROTAC) compound termed ?JQAD1? that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP compensates. Comparing HAT inhibition and EP300-specific degradation, we identified a non-catalytic role for EP300 in promoting MYCN expression and repression of apoptosis.
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| Overall design |
ChIP-Seq targeting histone acetyltransferases and associated acetylated histones in neuroblastoma cell lines
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| Contributor(s) |
Durbin AD, Wang T, Wimalasena VK, Zimmerman MW, Li D, Dharia NV, Mariani L, Shendy NA, Nance S, Patel A, Shao Y, Mundada M, Maxham L, Park P, Sigua LH, Morita K, Conway AS, Robichaud AL, Perez-Atayde A, Bikowitz M, Quinn T, Wiest O, Easton J, Schönbrunn E, Bulyk ML, Abraham BJ, Stegmaier K, Look AT, Qi J |
| Citation(s) |
34772733 |
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| Submission date |
Oct 19, 2020 |
| Last update date |
Feb 08, 2022 |
| Contact name |
Brian J Abraham |
| Organization name |
St. Jude Children's Research Hospital
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| Department |
Computational Biology
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| Street address |
262 Danny Thomas Blvd
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| City |
Memphis |
| State/province |
TN |
| ZIP/Postal code |
38112 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (6)
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| This SubSeries is part of SuperSeries: |
| GSE159617 |
EP300 selectively controls the enhancer landscape of MYCN-amplified neuroblastoma |
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| Relations |
| BioProject |
PRJNA670014 |
| SRA |
SRP287877 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE159613_RAW.tar |
497.2 Mb |
(http)(custom) |
TAR (of WIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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