The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer
Susmita G. Ramanand, … , Michael Q. Zhang, Ram S. Mani
Susmita G. Ramanand, … , Michael Q. Zhang, Ram S. Mani
Published April 28, 2020
Citation Information: J Clin Invest. 2020;130(8):3987-4005. https://doi.org/10.1172/JCI134260.
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The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer

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.

Authors

Susmita G. Ramanand, Yong Chen, Jiapei Yuan, Kelly Daescu, Maryou B.K. Lambros, Kathleen E. Houlahan, Suzanne Carreira, Wei Yuan, GuemHee Baek, Adam Sharp, Alec Paschalis, Mohammed Kanchwala, Yunpeng Gao, Adam Aslam, Nida Safdar, Xiaowei Zhan, Ganesh V. Raj, Chao Xing, Paul C. Boutros, Johann de Bono, Michael Q. Zhang, Ram S. Mani

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Figure 3

Transcriptional regulation of AR and FOXA1 loci.

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Transcriptional regulation of AR and FOXA1 loci. (A and B) Integrated ge...
(A and B) Integrated genome view of the AR gene and its adjacent regions from –1400 kb to +400 kb in LNCaP and VCaP cells. RNA Pol II ChIA-PET, RNA-Seq and CTCF, FOXA1, AR, H3K27ac, and RNA Pol II ChIP-Seq data are shown. In addition, AR ChIA-PET, phospho–RNA Pol II, and ERG ChIP-Seq are shown for VCaP cells. The AR gene and upstream regions are highlighted in light blue. (C) Summary of the copy number aberrations associated with the AR and its enhancers. Heatmap shows shows the aCGH high-density probes for 27 patients with mCRPC. Gains are depicted in pink and losses in light blue, whereas amplifications are shown in red and deep deletions in dark blue. Each column is a probe in the aCGH platform, and each row represents a sample. Probes that cover the EDA2R, AR, and regions of the enhancer peaks are shown. (D) Schematic representation of a deletion between the AR gene and its enhancers. (E) Comparison of RNA Pol II–associated chromatin interactions at the FOXA1 locus and its adjacent regions in the 4 cell lines.