The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer
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
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
View: Text | PDF
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

×

Figure 7

Evaluation of RNA Pol II–associated peaks and interaction with 122 prostate-specific germline SNP locations.

Options: View larger image (or click on image) Download as PowerPoint
Evaluation of RNA Pol II–associated peaks and interaction with 122 prost...
(A) Peak analysis. The red dashed lines indicate the observed number of peaks containing SNPs for each cell line. The histograms illustrate the results from 10,000 simulations that assessed the expected number of peaks containing SNPs. The mean of the simulations is shown with a dashed black line. ***P < 0.001, for significant differences between the expected and observed values. RWPE-1, LNCaP, VCaP, and DU145 have 17, 13, 14, and 4 peaks that overlap SNPs, respectively. The black dashed lines indicate the expected number of overlapping peaks (the mean of all the simulations). The expected values for RWPE-1, LNCaP, VCaP, and DU145 cells are 4.88, 4.09, 4.03, and 3.44, respectively. (B) Interaction analysis. The same procedure was repeated except using only the peaks involved in interactions. The red dashed lines indicate the observed number of SNPs, and the black dashed lines show the expected values. *P < 0.05 and ***P < 0.001, for significant differences between the expected and observed values. RWPE-1, LNCaP, VCaP, and DU145 cells had an observed value of 10, 9, 5, and 1, respectively, as indicated by the red dashed lines. The expected values for RWPE-1, LNCaP, VCaP, and DU145 cells are indicated by the black dashed lines and were 1.81, 2.17, 2.60, and 1.30, respectively. (C) Enrichment analysis. Fisher’s enrichment analysis was performed to compare the number of SNP-positive peaks with the rest of the genome as well as to compare the number of SNP-positive and interaction-positive peaks with the rest of the genome. ***P < 0.001, for significant enrichment. Fisher’s exact test was used to determine the P values for C. Empirical method was used to determine the P values for A and B.