Document Type

Article

Version Deposited

Published Version

Publication Date

8-3-2020

Publication Title

The Journal of Clinical Investigation

DOI

10.1172/JCI134260

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.

Comments

"Authors are permitted to post manuscripts on bioRxiv and medRxiv, and are also permitted to post the final published version of the manuscript in institutional repositories." (from https://www.jci.org/kiosks/about)

Published Citation

Ramanand, S. G., Chen, Y., Zhang, M. Q., Mani, R. S, et al. (2020). The landscape of RNA polymerase II–associated chromatin interactions in prostate cancer. Journal of Clinical Investigation 130(8):3987-4005. https://doi.org/10.1172/JCI134260.

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