RT Journal
A1 Zhang, Zhizhuo
A1 Chng, Kern Rei
A1 Lingadahalli, Shreyas
A1 Chen, Zikai
A1 Liu, Mei Hui
A1 Do, Huy Hoang
A1 Cai, Shaojiang
A1 Rinaldi, Nicola
A1 Poh, Huay Mei
A1 Li, Guoliang
A1 Sung, Ying Ying
A1 Heng, Charlie L.
A1 Core, Leighton J.
A1 Tan, Si Kee
A1 Ruan, Xiaoan
A1 Lis, John T.
A1 Kellis, Manolis
A1 Ruan, Yijun
A1 Sung, Wing-Kin
A1 Cheung, Edwin
T1 An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells
JF Genome Research 
JO Genome Research 
YR 2019 
FD January 03 
DO 10.1101/gr.230243.117 
UL http://genome.cshlp.org/content/early/2019/01/21/gr.230243.117.abstract 
AB 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.