TY - JOUR
T1 - The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer
AU - Ramanand, Susmita G.
AU - Chen, Yong
AU - Yuan, Jiapei
AU - Daescu, Kelly
AU - Lambros, Maryou B.K.
AU - Houlahan, Kathleen E.
AU - Carreira, Suzanne
AU - Yuan, Wei
AU - Baek, Guem Hee
AU - Sharp, Adam
AU - Paschalis, Alec
AU - Kanchwala, Mohammed
AU - Gao, Yunpeng
AU - Aslam, Adam
AU - Safdar, Nida
AU - Zhan, Xiaowei
AU - Raj, Ganesh V.
AU - Xing, Chao
AU - Boutros, Paul C.
AU - de Bono, Johann
AU - Zhang, Michael Q.
AU - Mani, Ram S.
N1 - Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.
PY - 2020/8/3
Y1 - 2020/8/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI134260
DO - 10.1172/JCI134260
M3 - Article
C2 - 32343676
AN - SCOPUS:85086519430
SN - 0021-9738
VL - 140
SP - 3987
EP - 4005
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -