Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA

Nicolas Léveillé; Carlos A Melo; Koos Rooijers; Angel Díaz-Lagares; Sonia A Melo; Gozde Korkmaz; Rui Lopes; Farhad Akbari Moqadam; Ana R Maia; Patrick J Wijchers; Geert Geeven; Monique L den Boer; Raghu Kalluri; Wouter de Laat; Manel Esteller; Reuven Agami

doi:10.1038/ncomms7520

Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA

Nicolas Léveillé, Carlos A Melo, Koos Rooijers, Angel Díaz-Lagares, Sonia A Melo, Gozde Korkmaz, Rui Lopes, Farhad Akbari Moqadam, Ana R Maia, Patrick J Wijchers, Geert Geeven, Monique L den Boer, Raghu Kalluri, Wouter de Laat, Manel Esteller, Reuven Agami

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

146 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	6520
Tijdschrift	Nature Communications
Volume	6
DOI's	https://doi.org/10.1038/ncomms7520
Status	Gepubliceerd - 2015

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10.1038/ncomms7520

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Léveillé, N., Melo, C. A., Rooijers, K., Díaz-Lagares, A., Melo, S. A., Korkmaz, G., Lopes, R., Akbari Moqadam, F., Maia, A. R., Wijchers, P. J., Geeven, G., den Boer, M. L., Kalluri, R., de Laat, W., Esteller, M., & Agami, R. (2015). Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA. Nature Communications, 6, 6520. https://doi.org/10.1038/ncomms7520

@article{938461f1ef4d42ba9a182c1bb37f5bd9,

title = "Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA",

abstract = "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.",

author = "Nicolas L{\'e}veill{\'e} and Melo, {Carlos A} and Koos Rooijers and Angel D{\'i}az-Lagares and Melo, {Sonia A} and Gozde Korkmaz and Rui Lopes and {Akbari Moqadam}, Farhad and Maia, {Ana R} and Wijchers, {Patrick J} and Geert Geeven and {den Boer}, {Monique L} and Raghu Kalluri and {de Laat}, Wouter and Manel Esteller and Reuven Agami",

year = "2015",

doi = "10.1038/ncomms7520",

language = "English",

volume = "6",

pages = "6520",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Léveillé, N, Melo, CA, Rooijers, K, Díaz-Lagares, A, Melo, SA, Korkmaz, G, Lopes, R, Akbari Moqadam, F, Maia, AR, Wijchers, PJ, Geeven, G, den Boer, ML, Kalluri, R, de Laat, W, Esteller, M & Agami, R 2015, 'Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA', Nature Communications, vol. 6, blz. 6520. https://doi.org/10.1038/ncomms7520

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 - Akbari Moqadam, Farhad

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

PY - 2015

Y1 - 2015

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.

U2 - 10.1038/ncomms7520

DO - 10.1038/ncomms7520

M3 - Article

C2 - 25813522

SN - 2041-1723

VL - 6

SP - 6520

JO - Nature Communications

JF - Nature Communications

ER -

Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA

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