Publications Repository

Publications Repository

View item 
  •   Home
  • ICR Divisions
  • Cancer Therapeutics
  • View item
  • Home
  • ICR Divisions
  • Cancer Therapeutics
  • View item
JavaScript is disabled for your browser. Some features of this site may not work without it.

The landscape of RNA polymerase II-associated chromatin interactions in prostate cancer.

Thumbnail
View/Open
Published version (11.68Mb)
Date
2020-08
ICR Author
Paschalis, Alec
Sharp, Adam
Carreira, Suzanne
De Bono, Johann
Author
Ramanand, SG
Chen, Y
Yuan, J
Daescu, K
Lambros, MB
Houlahan, KE
Carreira, S
Yuan, W
Baek, G
Sharp, A
Paschalis, A
Kanchwala, M
Gao, Y
Aslam, A
Safdar, N
Zhan, X
Raj, GV
Xing, C
Boutros, PC
de Bono, J
Zhang, MQ
Mani, RS
Show allShow less
Type
Journal Article
Metadata
Show full item record
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.
URI
https://repository.icr.ac.uk/handle/internal/4013
DOI
https://doi.org/10.1172/jci134260
Collections
  • Cancer Therapeutics
  • Clinical Studies
Research team
Cancer Biomarkers
Prostate Cancer Targeted Therapy Group
Translational Therapeutics
Language
eng
Date accepted
2020-04-23
License start date
2020-08
Citation
The Journal of clinical investigation, 2020, 130 (8), pp. 3987 - 4005

Browse

All of ICR repositoryICR DivisionsBy issue dateAuthorsTitlesPublication TypesThis collectionBy issue dateAuthorsTitlesPublication Types
  • Login
  • Registered office: The Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP
    A Charity, Not for Profit. Company Limited by Guarantee.
    Registered in England No. 534147. VAT Registration No. GB 849 0581 02.