TY - JOUR
T1 - Ligand-dependent enhancer activation regulated by topoisomerase-I activity
AU - Puc, Janusz
AU - Kozbial, Piotr
AU - Li, Wenbo
AU - Tan, Yuliang
AU - Liu, Zhijie
AU - Suter, Tom
AU - Ohgi, Kenneth A.
AU - Zhang, Jie
AU - Aggarwal, Aneel K.
AU - Rosenfeld, Michael G.
N1 - Funding Information:
We thank Dr. Bogdan Tanasa and Daria Merkurjev for help with statistical analyses, Charles Nelson for cell-culture assistance, Tara Rambaldo for help with cell-cycle analysis, and Janet Hightower for assistance with figure preparation. We are particularly grateful to Dr. E. Peter Geiduschek for a critical reading of the manuscript and Drs. Kalotina Machini and Patricia Cortes for discussions and helpful suggestions and thank the members of the M.G.R. laboratory for their comments on the work. This work was supported by grants from NIH and NCI to M.G.R. (DK018477, HL065445, NS034934, GM104459, DK039949, DK074868, DK097748, and CA173903). J.P. was supported, in part, by a NIDDK Mentored Research Scientist Development Award (K01DK080180). M.G.R. is an Investigator with the HHMI.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/1/29
Y1 - 2015/1/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84922147486&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922147486&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2014.12.023
DO - 10.1016/j.cell.2014.12.023
M3 - Article
C2 - 26321332
AN - SCOPUS:84922147486
SN - 0092-8674
VL - 160
SP - 367
EP - 380
JO - Cell
JF - Cell
IS - 3
ER -