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| Status |
Public on Mar 07, 2013 |
| Title |
Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers [Affymetrix] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Chromatin regulators have become highly attractive targets for cancer therapy, yet many of these regulators are expressed in a broad range of healthy cells and contribute generally to gene expression. An important conundrum has thus emerged: how can inhibition of a general regulator of gene expression produce selective effects at specific oncogenes? Here we investigate how inhibition of the transcriptional coactivator BRD4 (Bromodomain containing 4) leads to selective inhibition of disease-critical oncogenes in a highly malignant blood cancer, multiple myeloma (MM). We found that BRD4 generally occupies the promoter elements of active genes together with the Mediator coactivator, but remarkably high levels of these two coactivator proteins were associated with a small set of exceptionally large enhancers. These super-enhancers are associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impact genes with super-enhancers, including the c-MYC oncogene. Super-enhancers were found at key oncogenic drivers in many other tumor cells. Thus, super-enhancers can regulate oncogenic drivers in tumor cells, which in some cells can be preferentially disrupted by BRD4 inhibition, which in turn contributes to the selective transcriptional effects observed at these oncogenes. These observations have implications for the discovery of novel cancer therapeutics directed at components of super-enhancers in diverse tumor types.
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| Overall design |
Gene expression profiling in multiple myeloma cells after BET-Bromodomain inhibition with JQ1
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| Contributor(s) |
Loven J, Hoke H, Lin CY, Young RA |
| Citation(s) |
23582323 |
| Submission date |
Mar 06, 2013 |
| Last update date |
May 18, 2016 |
| 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 |
| |
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| Platforms (1) |
| GPL16043 |
GeneChip® PrimeView™ Human Gene Expression Array (with External spike-in RNAs) |
|
| Samples (18)
|
| GSM1094087 |
500nm JQ1 30 minute treatment - replicate 2 |
| GSM1094088 |
500nm JQ1 1 hour treatment - replicate 1 |
| GSM1094089 |
500nm JQ1 1 hour treatment - replicate 2 |
| GSM1094090 |
500nm JQ1 3 hour treatment - replicate 1 |
| GSM1094091 |
500nm JQ1 3 hour treatment - replicate 2 |
| GSM1094092 |
500nm JQ1 6 hour treatment - replicate 1 |
| GSM1094093 |
500nm JQ1 6 hour treatment - replicate 2 |
| GSM1094094 |
5nm JQ1 6 hour treatment - replicate 1 |
| GSM1094095 |
5nm JQ1 6 hour treatment - replicate 2 |
| GSM1094096 |
50nm JQ1 6 hour treatment - replicate 1 |
| GSM1094097 |
50nm JQ1 6 hour treatment - replicate 2 |
| GSM1094098 |
5000nm JQ1 6 hour treatment - replicate 1 |
| GSM1094099 |
5000nm JQ1 6 hour treatment - replicate 2 |
| GSM1094100 |
DMSO 6 hour treatment - replicate 1 |
| GSM1094101 |
DMSO 6 hour treatment - replicate 2 |
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| This SubSeries is part of SuperSeries: |
| GSE44931 |
Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers |
|
| Relations |
| BioProject |
PRJNA192546 |
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