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Series GSE30700 Query DataSets for GSE30700
Status Public on Jul 14, 2013
Title The Bromodomain protein Brd4 Insulates Chromatin from DNA Damage Signaling through Acetyl-Lysine Binding
Organism Homo sapiens
Experiment type Expression profiling by array
Summary DNA damage activates a complex signaling network in cells that blocks cell cycle progression, recruits factors involved in DNA repair, and/or triggers programs that control senescence or programmed cell death. Alterations in chromatin structure are known to be important for the initiation and propagation of the DNA damage response, although the molecular details are unclear. We investigated the role of chromatin structure in the DNA damage response by monitoring multiple timedependent checkpoint signaling and response events with a high-content multiplex image-based RNAi screen of chromatin modifying and interacting genes. We discovered that Brd4, a double bromodomain-containing protein, functions as an endogenous inhibitor of DNA damage signaling by binding to acetylated histones at sites of open chromatin and altering chromatin accessibility. Loss of Brd4 or disruption of acetyl-lysine binding results in an increase in both the number and size of radiation-induced !H2AX nuclear foci while overexpression of a Brd4 splice isoform completely suppresses !H2AX formation, despite equivalent double strand break formation. Brd4 knock-down cells displayed altered chromatin structure, prolonged cell cycle checkpoint arrest and enhanced survival after irradiation, while overexpression of Brd4 isoform B results in enhanced radiationinduced lethality. Brd4 is the target of the t(15;19) chromosomal translocation in a rare form of cancer, NUT Midline Carcinoma. Acetyl lysine-bromodomain interactions of the Brd4-NUT fusion protein suppresses !H2AX foci in discrete nuclear compartments, rendering cells more radiosensitive, mimicking overexpression of Brd4 isoform B. NUT Midline Carcinoma is sensitive to radiotherapy, however tumor material from this rare cancer is scarce. We therefore investigated Brd4 expression in another human cancer commonly treated with radiotherapy, glioblastoma multiforme, and found that expression of Brd4 isoform B correlated specifically with treatment response to radiotherapy. These data implicate Brd4 as an endogenous insulator of DNA damage signaling through recognition of epigenetic modifications in chromatin and suggest that expression of the Brd4 in human cancer can modulate the clinical response to DNA-damaging cancer therapy.
 
Overall design Two replicates each of U2OS cells expressing either Brd4 shRNA or a control shRNA
 
Contributor(s) Floyd SR, Pacold ME, Clarke SM, Blake EJ, Fydrych A, Ho R, Lee MJ, Root DE, Carpenter AE, Sabatini DM, French CA, Bradner JE, Chen CC, Yaffe MB
Citation(s) 23728299
Submission date Jul 15, 2011
Last update date Dec 06, 2018
Contact name Charles Arthur Whittaker
E-mail(s) charliew@mit.edu
Organization name Koch Institute
Street address 77 Mass Ave 76-189
City Cambridge
State/province MA
ZIP/Postal code 02152
Country USA
 
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (4)
GSM761595 U2OScells_StablyExpressingBrd4shRNA_rep1
GSM761596 U2OScells_StablyExpressingBrd4shRNA_rep2
GSM761597 U2OScells_StablyExpressingControlshRNA_rep1
Relations
BioProject PRJNA144397

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE30700_RAW.tar 7.5 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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