An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells
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 limite...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Cold Spring Harbor Laboratory
2020
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| Online Access: | https://hdl.handle.net/1721.1/127808 |
| _version_ | 1826215481940377600 |
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| author | Zhang, Zhizhuo Chng, Kern Rei Lingadahalli, Shreyas Chen, Zikai Liu, Mei Hui Do, Huy Hoang Cai, Shaojiang Rinaldi, Nicola Poh, Huay Mei Li, Guoliang Sung, Ying Ying Heng, Charlie L. Core, Leighton J. Tan, Si Kee Ruan, Xiaoan Lis, John T. Kellis, Manolis Ruan, Yijun Sung, Wing-Kin Cheung, Edwin |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Zhang, Zhizhuo Chng, Kern Rei Lingadahalli, Shreyas Chen, Zikai Liu, Mei Hui Do, Huy Hoang Cai, Shaojiang Rinaldi, Nicola Poh, Huay Mei Li, Guoliang Sung, Ying Ying Heng, Charlie L. Core, Leighton J. Tan, Si Kee Ruan, Xiaoan Lis, John T. Kellis, Manolis Ruan, Yijun Sung, Wing-Kin Cheung, Edwin |
| author_sort | Zhang, Zhizhuo |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:31:09Z |
| format | Article |
| id | mit-1721.1/127808 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:31:09Z |
| publishDate | 2020 |
| publisher | Cold Spring Harbor Laboratory |
| record_format | dspace |
| spelling | mit-1721.1/1278082022-10-02T08:13:21Z An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells Zhang, Zhizhuo Chng, Kern Rei Lingadahalli, Shreyas Chen, Zikai Liu, Mei Hui Do, Huy Hoang Cai, Shaojiang Rinaldi, Nicola Poh, Huay Mei Li, Guoliang Sung, Ying Ying Heng, Charlie L. Core, Leighton J. Tan, Si Kee Ruan, Xiaoan Lis, John T. Kellis, Manolis Ruan, Yijun Sung, Wing-Kin Cheung, Edwin Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory 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. 2020-10-05T19:06:42Z 2020-10-05T19:06:42Z 2019-01 2017-09 2019-06-07T15:51:14Z Article http://purl.org/eprint/type/JournalArticle 1088-9051 1549-5469 https://hdl.handle.net/1721.1/127808 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. en http://dx.doi.org/10.1101/gr.230243.117 Genome Research Creative Commons Attribution NonCommercial License 4.0 https://creativecommons.org/licenses/by-nc/4.0/ application/pdf Cold Spring Harbor Laboratory Cold Spring Harbor Laboratory Press |
| spellingShingle | Zhang, Zhizhuo Chng, Kern Rei Lingadahalli, Shreyas Chen, Zikai Liu, Mei Hui Do, Huy Hoang Cai, Shaojiang Rinaldi, Nicola Poh, Huay Mei Li, Guoliang Sung, Ying Ying Heng, Charlie L. Core, Leighton J. Tan, Si Kee Ruan, Xiaoan Lis, John T. Kellis, Manolis Ruan, Yijun Sung, Wing-Kin Cheung, Edwin An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells |
| title | An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells |
| title_full | An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells |
| title_fullStr | An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells |
| title_full_unstemmed | An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells |
| title_short | An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells |
| title_sort | ar erg transcriptional signature defined by long range chromatin interactomes in prostate cancer cells |
| url | https://hdl.handle.net/1721.1/127808 |
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