TY - JOUR
T1 - Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA
AU - Léveillé, Nicolas
AU - Melo, Carlos A.
AU - Rooijers, Koos
AU - Díaz-Lagares, Angel
AU - Melo, Sonia A.
AU - Korkmaz, Gozde
AU - Lopes, Rui
AU - Moqadam, Farhad Akbari
AU - Maia, Ana R.
AU - Wijchers, Patrick J.
AU - Geeven, Geert
AU - Den Boer, Monique L.
AU - Kalluri, Raghu
AU - De Laat, Wouter
AU - Esteller, Manel
AU - Agami, Reuven
N1 - Funding Information: We thank Nuno Barros for graphical support. This work was supported by funds from the Fundac¸ão para a Ciência e a Tecnologia, Portugal to C.A.M. (SFRH/BD/33472/2008) and R.L. (SFRH/BD/74476/2010; POPH/FSE), Human Frontiers Program to S.A.M., the Netherlands Organization for Scientific Research (‘NWO’ Vidi grant) to M.L.dB. and F.A.M., ‘Sara Borrell’ postdoctoral contract (CD12/00738) from the ISCIII at the Spanish Ministry of Economy and Competitiveness to A.D.L., European Research Council (ERC) Advanced Grant EPINORC (# 268626) to M.E. and the European Research Council (ERC) Advanced Grant EnhReg to R.A. Publisher Copyright: © 2015 Macmillan Publishers Limited.
PY - 2015/3
Y1 - 2015/3
N2 - p53 binds enhancers to regulate key target genes. Here, we globally mapped p53-regulated enhancers by looking at enhancer RNA (eRNA) production. Intriguingly, while many p53-induced enhancers contained p53-binding sites, most did not. As long non-coding RNAs (lncRNAs) are prominent regulators of chromatin dynamics, we hypothesized that p53-induced lncRNAs contribute to the activation of enhancers by p53. Among p53-induced lncRNAs, we identified LED and demonstrate that its suppression attenuates p53 function. Chromatin-binding and eRNA expression analyses show that LED associates with and activates strong enhancers. One prominent target of LED was located at an enhancer region within CDKN1A gene, a potent p53-responsive cell cycle inhibitor. LED knockdown reduces CDKN1A enhancer induction and activity, and cell cycle arrest following p53 activation. Finally, promoter-associated hypermethylation analysis shows silencing of LED in human tumours. Thus, our study identifies a new layer of complexity in the p53 pathway and suggests its dysregulation in cancer.
AB - p53 binds enhancers to regulate key target genes. Here, we globally mapped p53-regulated enhancers by looking at enhancer RNA (eRNA) production. Intriguingly, while many p53-induced enhancers contained p53-binding sites, most did not. As long non-coding RNAs (lncRNAs) are prominent regulators of chromatin dynamics, we hypothesized that p53-induced lncRNAs contribute to the activation of enhancers by p53. Among p53-induced lncRNAs, we identified LED and demonstrate that its suppression attenuates p53 function. Chromatin-binding and eRNA expression analyses show that LED associates with and activates strong enhancers. One prominent target of LED was located at an enhancer region within CDKN1A gene, a potent p53-responsive cell cycle inhibitor. LED knockdown reduces CDKN1A enhancer induction and activity, and cell cycle arrest following p53 activation. Finally, promoter-associated hypermethylation analysis shows silencing of LED in human tumours. Thus, our study identifies a new layer of complexity in the p53 pathway and suggests its dysregulation in cancer.
UR - http://www.scopus.com/inward/record.url?scp=84925760606&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/ncomms7520
DO - https://doi.org/10.1038/ncomms7520
M3 - Article
C2 - 25813522
SN - 2041-1723
VL - 6
JO - Nature communications
JF - Nature communications
M1 - 6520
ER -