An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells
Name
Genome Res.-2019-Zhang-223-35.pdf
Description
Published version
Size
10.76 MB
Format
Adobe PDF
Checksum (MD5)
d5acffd2265f18dc549788e974f93c42
Author(s)
Zhang, Zhizhuo
Chng, Kern Rei
Lingadahalli, Shreyas
Chen, Zikai
Liu, Mei Hui
Do, Huy Hoang
Cai, Shaojiang
Rinaldi, Nicola
Poh, Huay Mei
Li, Guoliang
Date Issued
January 2019
Journal
Genome Research
Publisher
Cold Spring Harbor Laboratory
Citation
Zhang, Zhizhuo et al. "An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells." Genome Research 29, 2 (January 2019): 223-235 © 2019 Zhang et al.
Version
Final published version
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 ARERG- centric higher-order chromatin structure that drives coordinated gene expression in prostate cancer progression and the identification of potential target genes for therapeutic intervention.
MIT Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Terms of Use
Creative Commons Attribution NonCommercial License 4.0
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DOI of Published Version
https://doi.org/10.1101/gr.230243.117
