An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells
- Zhizhuo Zhang1,2,3,9,
- Kern Rei Chng4,9,
- Shreyas Lingadahalli5,6,9,
- Zikai Chen4,5,6,
- Mei Hui Liu4,10,
- Huy Hoang Do4,
- Shaojiang Cai4,
- Nicola Rinaldi2,
- Huay Mei Poh4,
- Guoliang Li4,7,
- Ying Ying Sung4,
- Charlie L. Heng4,
- Leighton J. Core8,11,
- Si Kee Tan4,
- Xiaoan Ruan4,12,
- John T. Lis8,
- Manolis Kellis2,3,
- Yijun Ruan4,12,
- Wing-Kin Sung1,4 and
- Edwin Cheung4,5,6
- 1School of Computing, National University of Singapore, Singapore 117417;
- 2Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 3Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA;
- 4Genome Institute of Singapore, Singapore 138672;
- 5Cancer Centre, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China;
- 6Centre of Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Taipa, Macau 999078, China;
- 7National Key Laboratory of Crop Genetic Improvement, Agricultural Bioinformatics Key Laboratory of Hubei Province, College of Informatics, Huazhong Agricultural University, Wuhan, Hubei 430070, China;
- 8Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York 14853, USA
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↵9 These authors contributed equally to this work.
Abstract
The aberrant activities of transcription factors such as the androgen receptor (AR) underpin prostate cancer development. While the AR cis-regulation has been extensively studied in prostate cancer, information pertaining to the spatial architecture of the AR transcriptional circuitry remains limited. In this paper, we propose a novel framework to profile long-range chromatin interactions associated with AR and its collaborative transcription factor, erythroblast transformation-specific related gene (ERG), using chromatin interaction analysis by paired-end tag (ChIA-PET). We identified ERG-associated long-range chromatin interactions as a cooperative component in the AR-associated chromatin interactome, acting in concert to achieve coordinated regulation of a subset of AR target genes. Through multifaceted functional data analysis, we found that AR-ERG interaction hub regions are characterized by distinct functional signatures, including bidirectional transcription and cotranscription factor binding. In addition, cancer-associated long noncoding RNAs were found to be connected near protein-coding genes through AR-ERG looping. Finally, we found strong enrichment of prostate cancer genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) at AR-ERG co-binding sites participating in chromatin interactions and gene regulation, suggesting GWAS target genes identified from chromatin looping data provide more biologically relevant findings than using the nearest gene approach. Taken together, our results revealed an AR-ERG-centric higher-order chromatin structure that drives coordinated gene expression in prostate cancer progression and the identification of potential target genes for therapeutic intervention.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.230243.117.
- Received September 17, 2017.
- Accepted December 13, 2018.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
