|
| Status |
Public on Oct 25, 2021 |
| Title |
Retinoic acid rewires the adrenergic core regulatory circuitry of neuroblastoma but can be subverted by enhancer hijacking of MYC or MYCN (CUT&RUN-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that incorporate MYCN to drive the oncogenic gene expression program. For neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation in both primary neuroblastomas and cell lines; however, the underlying mechanisms remain unclear. Here we show that when MYCN-amplified neuroblastomas cells are treated with all-trans retinoic acid (ATRA), they undergo modifications of histone H3K27 acetylation and methylation that decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of expression of MEIS1, HIC1 and SOX4. These findings indicate that treatment with ATRA can reprogram the enhancer landscape to collapse the adrenergic CRC, which downregulates MYCN expression, while upregulating a new “retino-sympathetic” CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids against high-risk neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of gene amplification.
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| |
|
| Overall design |
CUT&RUN-Seq against transcription factors in neuroblastoma cell line BE2C
|
| |
|
| Contributor(s) |
Zimmerman MW, Durbin AD, He S, Berezovskaya A, Oppel F, Shi H, Tao T, Li Z, Liu Y, Zhang J, Young RA, Abraham BJ, Look AT |
| Citation(s) |
34669465 |
| |
| Submission date |
Mar 25, 2021 |
| Last update date |
Oct 26, 2021 |
| Contact name |
Richard A Young |
| E-mail(s) |
young_computation@wi.mit.edu
|
| Phone |
617-258-5219
|
| Organization name |
Whitehead Institute for Biomedical Research
|
| Lab |
Young Lab
|
| Street address |
9 Cambridge Center
|
| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (10)
|
|
| This SubSeries is part of SuperSeries: |
| GSE155002 |
Retinoic acid rewires the adrenergic core regulatory circuitry of neuroblastoma but can be subverted by enhancer hijacking of MYC or MYCN |
|
| Relations |
| BioProject |
PRJNA717224 |
| SRA |
SRP312116 |
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