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| Status |
Public on Sep 18, 2017 |
| Title |
BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Cancer arises from the malignant interplay between oncogenic signaling and cell specification. Transcriptionally activated stem, growth and survival programs reshape an epigenomic identity defined by a transcriptional core regulatory circuitry. To study and disrupt oncogenic transcription, we first created inhibitors of BET bromodomains. Selective antagonism of oncogenic transcriptional signaling arises from bromodomain-specific activity. Recently, we innovated a strategy to induce selective and pronounced degradation of BET coactivator proteins via phthalimide conjugation for E3 ubiquitin ligase recruitment. Degraders of BET bromdomains (dBETs) exhibited superior efficacy to bromodomain inhibitors in cultivated leukemia cells, through unknown mechanisms. Here, we use chemically optimized small-molecule degronimids and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in the control of global productive transcriptional elongation. Rapid loss of BRD4 attenuates phosphorylation of the carboxy-terminal domain of RNA polymerase II, independent of genomewide recruitment of CDK9 to promoters, leading to a collapse of the transcriptional core regulatory circuitry. These mechanistic studies are performed in translational models of T-cell acute lymphoblastic leukemia, a disease emblematic for transcriptional addiction, to establish a rationale for human clinical investigation.
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| |
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| Overall design |
ChIP-Seq for BRD4, CDK9, and RNA Pol II in MOLT4 T-ALL cells treated with JQ1, dBET6, or DMSO.
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| |
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| Contributor(s) |
Winter GE, Buckley DL, Erb MA, Bradner JE |
| Citation missing |
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| Submission date |
Mar 16, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
James Bradner |
| E-mail(s) |
bradner_computation@dfci.harvard.edu
|
| Organization name |
Dana-Farber Cancer Institute
|
| Department |
Medical Oncology
|
| Lab |
Bradner Lab
|
| Street address |
450 Brookline
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
|
| Samples (17)
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| This SubSeries is part of SuperSeries: |
| GSE79290 |
BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment |
|
| Relations |
| BioProject |
PRJNA315416 |
| SRA |
SRP071858 |
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