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Series GSE79271 Query DataSets for GSE79271
Status Public on Sep 18, 2017
Title BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment [NET-seq]
Organism Homo sapiens
Experiment type Expression 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.
Overall design NET-Seq for DMSO, dBET6, or JQ1 treated MOLT4 cells
Contributor(s) Winter GE, Buckley DL, Bradner JE
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Submission date Mar 16, 2016
Last update date May 15, 2019
Contact name James Bradner
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 (6)
GSM2090425 NET-seq DMSO Rep1
GSM2090426 NET-seq DMSO Rep2
GSM2090427 NET-seq JQ1 Rep1
This SubSeries is part of SuperSeries:
GSE79290 BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment
BioProject PRJNA315415
SRA SRP071861

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Supplementary file Size Download File type/resource
GSE79271_RAW.tar 284.5 Mb (http)(custom) TAR (of BEDGRAPH)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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