Ligand-dependent enhancer activation regulated by topoisomerase-I activity

Janusz Puc, Piotr Kozbial, Wenbo Li, Yuliang Tan, Zhijie Liu, Tom Suter, Kenneth A. Ohgi, Jie Zhang, Aneel K. Aggarwal, Michael G. Rosenfeld

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

The discovery that enhancers are regulated transcription units, encoding eRNAs, has raised new questions about the mechanisms of their activation. Here, we report an unexpected molecular mechanism that underlies ligand-dependent enhancer activation, based on DNA nicking to relieve torsional stress from eRNA synthesis. Using dihydrotestosterone (DHT)-induced binding of androgen receptor (AR) to prostate cancer cell enhancers as a model, we show rapid recruitment, within minutes, of DNA topoisomerase I (TOP1) to a large cohort of AR-regulated enhancers. Furthermore, we show that the DNA nicking activity of TOP1 is a prerequisite for robust eRNA synthesis and enhancer activation and is kinetically accompanied by the recruitment of ATR and the MRN complex, followed by additional components of DNA damage repair machinery to the AR-regulated enhancers. Together, our studies reveal a linkage between eRNA synthesis and ligand-dependent TOP1-mediated nicking - a strategy exerting quantitative effects on eRNA expression in regulating AR-bound enhancer-dependent transcriptional programs.

Original languageEnglish (US)
Pages (from-to)367-380
Number of pages14
JournalCell
Volume160
Issue number3
DOIs
StatePublished - Jan 29 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Puc, J., Kozbial, P., Li, W., Tan, Y., Liu, Z., Suter, T., Ohgi, K. A., Zhang, J., Aggarwal, A. K., & Rosenfeld, M. G. (2015). Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell, 160(3), 367-380. https://doi.org/10.1016/j.cell.2014.12.023