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.
authors: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Nicolas
authors: N
authors: Léveillé
authors: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.|Doctoral Programme in Biomedicine and Experimental Biology, Centre for Neuroscience and Cell Biology, Coimbra University, 3004-504 Coimbra, Portugal.
authors: Carlos A
authors: CA
authors: Melo
authors: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Koos
authors: K
authors: Rooijers
authors: Division of Cancer Epigenetics, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia 08908, Spain.
authors: Angel
authors: A
authors: Díaz-Lagares
authors: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
authors: Sonia A
authors: SA
authors: Melo
authors: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Gozde
authors: G
authors: Korkmaz
authors: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Rui
authors: R
authors: Lopes
authors: Department of Pediatric Oncology and Hematology, Erasmus University Medical Center, Erasmus MC, 3015 CE Rotterdam, The Netherlands.
authors: Farhad Akbari
authors: FA
authors: Moqadam
authors: Department of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Ana R
authors: AR
authors: Maia
authors: Hubrecht Institute-KNAW, University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors: Patrick J
authors: PJ
authors: Wijchers
authors: Hubrecht Institute-KNAW, University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors: Geert
authors: G
authors: Geeven
authors: Department of Pediatric Oncology and Hematology, Erasmus University Medical Center, Erasmus MC, 3015 CE Rotterdam, The Netherlands.
authors: Monique L
authors: ML
authors: den Boer
authors: Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA.
authors: Raghu
authors: R
authors: Kalluri
authors: Hubrecht Institute-KNAW, University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors: Wouter
authors: W
authors: de Laat
authors: Division of Cancer Epigenetics, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia 08908, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia 08036, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia 08010, Spain.
authors: Manel
authors: M
authors: Esteller
authors: Division of Biological Stress Response, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.|Erasmus MC, Rotterdam University, 3000 CA Rotterdam, The Netherlands.
authors: Reuven
authors: R
authors: Agami
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D062085:RNA, Long Noncoding; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53