Functional mapping of androgen receptor enhancer activity

  • Wilbert T. Zwart (Creator)
  • Simon Linder (Netherlands Cancer Institute) (Creator)
  • Chia Chi Flora Huang (Creator)
  • Stephane Le Bihan (Contributor)
  • Faraz Hach (Contributor)
  • Umut Berkay Altıntaş (Creator)
  • Nathan A. Lack (Creator)
  • Dogancan Ozturan (Contributor)
  • Colin Collins (Creator)
  • Bengul Gokbayrak (Contributor)
  • Marlous Hoogstraat (Creator)
  • Mohammadali Saffarzadeh (Contributor)
  • Funda Sar (Creator)
  • Andries M. Bergman (Creator)
  • Suzan Stelloo (Creator)
  • Shreyas Lingadahalli (Contributor)
  • Martin E. Gleave (Creator)
  • Henk G. van der Poel (Contributor)
  • Tunç Morova (Contributor)
  • Brian McConeghy (Creator)
  • Eugene Hu (Creator)
  • Ivan Pak Lok Yu (Creator)
  • Felix Yi Chung Feng (Creator)
  • Eldon Emberly (Creator)



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.
Date made available12 May 2021
  • Functional mapping of androgen receptor enhancer activity

    Huang, C. C. F., Lingadahalli, S., Morova, T., Ozturan, D., Hu, E., Yu, I. P. L., Linder, S., Hoogstraat, M., Stelloo, S., Sar, F., van der Poel, H., Altintas, U. B., Saffarzadeh, M., Le Bihan, S., McConeghy, B., Gokbayrak, B., Feng, F. Y., Gleave, M. E., Bergman, A. M., Collins, C., & 4 othersHach, F., Zwart, W., Emberly, E. & Lack, N. A., 11 May 2021, In: Genome Biology. 22, 1, 26 p., 149.

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