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| Status |
Public on May 22, 2018 |
| Title |
Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma [array] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Transcriptional dysregulation plays a major role in the development and progression of human tumors such as pediatric neuroblastoma. Therefore, we sought to elucidate the relationship between genes required for neuroblastoma cell growth and survival and the transcriptional core regulatory circuitry (CRC) that controls the gene expression program. A genome-scale CRISPR-Cas9 screen for oncogenic dependencies revealed that 143 genes are essential for cell survival and growth in neuroblastoma relative to other cancers, including many super-enhancer (SE) regulated transcription factors. Genome-wide occupancy analysis of transcription factor binding demonstrated that at least six of these transcription factors were both dependency genes and components of the CRC in MYCN-amplified neuroblastoma including: HAND2, ISL1, PHOX2B, GATA3, TBX2, and MEIS2. Binding sites for these transcription factors were clustered within a few hundred base pairs in their own enhancers and the enhancers of downstream target genes, which surprisingly included 40% of the independently determined neuroblastoma dependency genes. This profound level of transcriptional control of oncogenesis through self-reinforcing transcriptional circuits led us to test combinatorial pharmacological inhibition of transcriptional initiation and elongation, which synergistically induced tumor cell death, supporting drugging transcription as a means to advance the treatment of high risk neuroblastoma.
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| Overall design |
Array-based expression profiling of neuroblastoma cells treated with JQ1 and 125nM THZ1 for up to 12hrs.
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| Contributor(s) |
Durbin AD, Zimmerman MW, Dharia NV, Abraham BJ, Balboni A, Weichert-Leahey N, He S, Krill-Burger JM, Vazquez F, Root DE, Tsherniak A, Hahn WC, Golub TR, Young RA, Stegmaier K, Look AT |
| Citation(s) |
30127528 |
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| Submission date |
Jan 09, 2018 |
| Last update date |
Aug 27, 2018 |
| Contact name |
Richard A Young |
| E-mail(s) |
[email protected]
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| Phone |
617-258-5219
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| Organization name |
Whitehead Institute for Biomedical Research
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| Lab |
Young Lab
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| Street address |
9 Cambridge Center
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (1) |
| GPL16043 |
GeneChip® PrimeView™ Human Gene Expression Array (with External spike-in RNAs) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE94824 |
Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma |
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| Relations |
| BioProject |
PRJNA429129 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE108914_RAW.tar |
30.2 Mb |
(http)(custom) |
TAR (of CEL) |
| GSE108914_matrix_complete.txt.gz |
3.6 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
| Processed data are available on Series record |
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