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Series GSE127957 Query DataSets for GSE127957
Status Public on Mar 26, 2020
Title Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [shRNA screen]
Organisms Homo sapiens; synthetic construct
Experiment type Other
Summary Next generation androgen receptor (AR) signaling inhibitors have significantly improved the survival of men with metastatic castration-resistant prostate cancer (mCPRC) but resistance remains a problem. Genomic alterations at the AR locus are present in ~50% of mCRPC patients, typically in association with large numbers of copy number gains and losses across the genome. To explore the functional consequences of these copy number alterations, we screened an shRNA library targeting all genes deleted in prostate cancer (the prostate cancer deletome: 4380 shRNAs targeting 730 genes) for next generation antiandrogen resistance using a clinically-validated model of enzalutamide-sensitive, AR-driven mCRPC LNCaP/AR. The Chromatin helicase DNA-binding factor (CHD1) scored as a top candidate and was validated in vitro and in vivo using multiple independent shRNAs and CRISPR guides. Mechanistically, CHD1 loss led to global changes in open and closed chromatin (ATAC-seq) as well as downregulation of canonical AR target genes upon the challenge of antiandrogen, despite robust AR expression. Integrative analysis of ATAC- and RNA-seq changes following CHD1 deletion identified 23 candidate transcription factor drivers of enzalutamide resistance. CRISPR-based unbiased functional screening identified 4 of these drivers may drive the AR-independent resistance, including glucocorticoid receptor (GR), BRN2, NR2F1 and TBX2. Genetic studies further establish that CHD1 loss confers antiandrogen resistance by converting mCRPC cells from AR-dependence to GR-dependence in one of the resistant LNCaP/AR clone. Thus, CHD1 functions as a molecular tuner to regulate chromatin plasticity and maintain oncogenic AR signaling, as well as AR dependency.
Overall design Identification of shRNA enrichment in enzalutamide resistant tumors compared to plasmid and pregraft samples.
The plasmid library was sequenced and provides the 'plasmid' samples. The library was transduced into human CRPC tumor cell line LNCaP/AR, these transduced LNCaP/AR cells serve as "pregrafts". Transduced LNCaP/AR cells were selected for 4 days using 2 ug/ml puromycin (Invitrogen) and 2 million cells were subcutaneously injected bilaterally into 5 castrated SCID mice. Genomic DNA from plasmids, pregrafts, and resistant tumors was isolated, and normalized reads of all shRNAs present in resistant tumors or starting materials (plasmids and pregrafts) were quantified using HiSeq 2500 sequencing of shRNA guide strands PCR amplified from the isolated genomic DNA.
Web link
Contributor(s) Mu P
Citation(s) 32220301
Submission date Mar 06, 2019
Last update date Jun 25, 2020
Contact name Ping Mu
Organization name UT Southwestern Medical Center
Department Human Oncology and Pathogenesis
Lab Mu Lab
Street address 6000 Harry Hines Blvd., NA6.308A
City Dallas
State/province TX
ZIP/Postal code 76092
Country USA
Platforms (2)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
GPL19604 Illumina HiSeq 2500 (synthetic construct)
Samples (408)
GSM3657231 pool_1_plasmid
GSM3657232 pool_10_plasmid
GSM3657233 pool_11_plasmid
This SubSeries is part of SuperSeries:
GSE126918 Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer
BioProject PRJNA525865
SRA SRP187768

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
GSE127957_RAW.tar 190.0 Kb (http)(custom) TAR (of TXT)
GSE127957_RIGER_Tumor_Reads_Matrix.txt.gz 276.7 Kb (ftp)(http) TXT
GSE127957_prostate_cancer_human_deletome.txt.gz 21.9 Kb (ftp)(http) TXT
GSE127957_tumor_TXT_files.tar.gz 227.5 Kb (ftp)(http) TAR
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Raw data are available in SRA
Processed data are available on Series record

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