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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Research Article Genetics Oncology

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 4

Chromatin interaction–associated transcriptional targets of the AR and FOXA1.

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Chromatin interaction–associated transcriptional targets of the AR and F...
(A) The expression of AR/FOXA1 target genes discovered by integrating RNA Pol II ChIA-PET with AR/FOXA1 ChIP-Seq was compared with the expression of genes that were nearest to AR/FOXA1 binding peaks according to ChIP-Seq data and randomly selected control genes in VCaP and LNCaP cells. The y axis represents expression levels, measured as FPKM transformed by log2. The box plots represent the median and 25% and 75% quantiles, with lines at 1.5 times the IQR. †P < 2.2 × 10–16, by Kolmogorov-Smirnov test). (B) Gene promoters that interact with AR, FOXA1, and AR-FOXA1 co-occupied regions in the RNA Pol II ChIA-PET data sets are shown in yellow. Gene promoters that interact with AR, FOXA1, and AR-FOXA1 co-occupied enhancers in the RNA Pol II ChIA-PET data sets are shown in orange. (C) Pathway analysis for gene promoters that interact with AR-FOXA1 co-occupied regions in LNCaP and VCaP cells in the RNA Pol II ChIA-PET data sets.