The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer
- 3 August 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (8), 3987-4005
- https://doi.org/10.1172/jci134260
Abstract
Transcriptional dysregulation is a hallmark of prostate cancer (PCa). We mapped the RNA Polymerase II (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 up-regulation of AR gene by increasing the total number of chromatin interaction modules comprising of 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 novel 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.Keywords
Funding Information
- Cancer Prevention and Research Institute of Texas (RP190454)
- National Institutes of Health (R00CA160640)
- National Institutes of Health (R01CA245294)
- U.S. Department of Defense (W81XWH-17-1-0675)
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