Functional mapping of androgen receptor enhancer activity

Chia Chi Flora Huang, Shreyas Lingadahalli, Tunc Morova, Dogancan Ozturan, Eugene Hu, Ivan Pak Lok Yu, Simon Linder, Marlous Hoogstraat, Suzan Stelloo, Funda Sar, Henk van der Poel, Umut Berkay Altintas, Mohammadali Saffarzadeh, Stephane Le Bihan, Brian McConeghy, Bengul Gokbayrak, Felix Y. Feng, Martin E. Gleave, Andries M. Bergman, Colin CollinsFaraz Hach, Wilbert Zwart, Eldon Emberly, Nathan A. Lack

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10–100× more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. Results: To characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. Conclusions: Using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.

Original languageEnglish
Article number149
Number of pages26
JournalGenome Biology
Volume22
Issue number1
DOIs
Publication statusPublished - 11 May 2021

Bibliographical note

Funding Information:
This work was supported by funding from KWF Dutch Cancer Society (10084 ALPE), TUBITAK 1001 (119Z279), NSERC, Prostate Cancer Foundation BC, and Astellas Pharma Inc.

Publisher Copyright:
© 2021, The Author(s).

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • Androgen receptor
  • Enhancers
  • Non-coding mutations
  • Prostate cancer
  • STARRseq

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