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Series GSE96652 Query DataSets for GSE96652
Status Public on Jul 25, 2017
Title Genomic profiling of H3K27ac and transcription factor binding in ERG-overexpressing prostate cancer
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Structural rearrangements leading to the TMPRSS2:ERG (T2E) fusion typify ~50% of prostate tumors and result in overexpression of the ERG transcription factor. Using T2E and non-T2E primary prostate tumors, we assessed the impact of ERG overexpression on chromatin by integrating ChIP-seq against H3K27ac, a chromatin modification found at active cis-regulatory elements, with paired genomic and expression data. We show that T2E tumors have a consistent and distinct cis-regulatory landscape to non-T2E tumors which drives their unique transcriptional profile. The T2E-specific cis-regulatory landscape is driven by ERG-mediated co-option of prostate master transcription factors HOXB13 and FOXA1 and is typified by Cluster Of Regulatory Elements (COREs)  including one spreading into the ERG locus of the structurally rearranged allele. This gives rise to a cis-regulatory element within the rearranged ERG gene that contributes to ERG overexpression. The unique cis-regulatory landscape in T2E primary prostate tumors also reveals the activation of the NOTCH signalling pathway. Accordingly, chemical NOTCH pathway inhibition limited the invasive nature of T2E prostate cancer cells, revealing an actionable vulnerability against T2E prostate tumors. Taken together, our work delineates the role of ERG over-expression in co-opting master transcription factors to deploy a unique cis-regulatory landscape inducing a dependency on NOTCH signaling in T2E prostate tumors.
 
Overall design Genomic profiles of H3K27ac in ERG overexpressing prostate cancer and prostate cancer without ERG overexpression. Genomic binding of AR, FOXA1, HOXB13 in 22Rv1 prostate cells and of HOXB13 in LNCaP prostate cells. Genomic binding of FOXA1 and HOXB13, as well as H3K27ac profiles, upon knockdown of ERG in VCaP prostate cells.
 
Contributor(s) Lupien M, Kron K
Citation(s) 28783165
Submission date Mar 15, 2017
Last update date May 15, 2019
Contact name Ken Kron
Organization name University Health Network
Street address 101 College Street, TMDT, 11th floor, room 11-601B
City Toronto
State/province ON
ZIP/Postal code M5G 1L7
Country Canada
 
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (44)
GSM2537212 AR ChIP-seq, rep1
GSM2537213 AR ChIP-seq, rep2
GSM2537214 HOXB13 ChIP-seq, rep1
Relations
BioProject PRJNA379295
SRA SRP101955

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE96652_22Rv1_AR_calledpeaks.bed.gz 313.2 Kb (ftp)(http) BED
GSE96652_22Rv1_FOXA1_calledpeaks.bed.gz 1.1 Mb (ftp)(http) BED
GSE96652_22Rv1_HOXB13_calledpeaks.bed.gz 217.9 Kb (ftp)(http) BED
GSE96652_LNCaP_HOXB13_calledpeaks.bed.gz 631.6 Kb (ftp)(http) BED
GSE96652_RAW.tar 977.7 Mb (http)(custom) TAR (of BED, BEDGRAPH)
SRA Run SelectorHelp
Processed data provided as supplementary file
Processed data are available on Series record
Raw data are available in SRA

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