The landscape of RNA polymerase II-associated chromatin interactions in prostate cancer.
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Embargo End Date
Authors
Ramanand, SG
Chen, Y
Yuan, J
Daescu, K
Lambros, MB
Houlahan, KE
Carreira, S
Yuan, W
Baek, G
Sharp, A
Paschalis, A
Kanchwala, M
Gao, Y
Aslam, A
Safdar, N
Zhan, X
Raj, GV
Xing, C
Boutros, PC
de Bono, J
Zhang, MQ
Mani, RS
Chen, Y
Yuan, J
Daescu, K
Lambros, MB
Houlahan, KE
Carreira, S
Yuan, W
Baek, G
Sharp, A
Paschalis, A
Kanchwala, M
Gao, Y
Aslam, A
Safdar, N
Zhan, X
Raj, GV
Xing, C
Boutros, PC
de Bono, J
Zhang, MQ
Mani, RS
Document Type
Journal Article
Date
2020-08-03
Date Accepted
2020-04-23
Abstract
Transcriptional dysregulation is a hallmark of prostate cancer (PCa). We mapped the RNA polymerase II-associated (RNA Pol II-associated) chromatin interactions in normal prostate cells and PCa cells. We discovered thousands of enhancer-promoter, enhancer-enhancer, as well as promoter-promoter chromatin interactions. These transcriptional hubs operate within the framework set by structural proteins - CTCF and cohesins - and are regulated by the cooperative action of master transcription factors, such as the androgen receptor (AR) and FOXA1. By combining analyses from metastatic castration-resistant PCa (mCRPC) specimens, we show that AR locus amplification contributes to the transcriptional upregulation of the AR gene by increasing the total number of chromatin interaction modules comprising the AR gene and its distal enhancer. We deconvoluted the transcription control modules of several PCa genes, notably the biomarker KLK3, lineage-restricted genes (KRT8, KRT18, HOXB13, FOXA1, ZBTB16), the drug target EZH2, and the oncogene MYC. By integrating clinical PCa data, we defined a germline-somatic interplay between the PCa risk allele rs684232 and the somatically acquired TMPRSS2-ERG gene fusion in the transcriptional regulation of multiple target genes - VPS53, FAM57A, and GEMIN4. Our studies implicate changes in genome organization as a critical determinant of aberrant transcriptional regulation in PCa.
Citation
The Journal of clinical investigation, 2020, 130 (8), pp. 3987 - 4005
Source Title
Publisher
AMER SOC CLINICAL INVESTIGATION INC
ISSN
0021-9738
eISSN
1558-8238
Collections
Research Team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Prostate Cancer Targeted Therapy Group
Translational Therapeutics