title: eRNAs are required for p53-dependent enhancer activity and gene transcription.
abstract: Binding within or nearby target genes involved in cell proliferation and survival enables the p53 tumor suppressor gene to regulate their transcription and cell-cycle progression. Using genome-wide chromatin-binding profiles, we describe binding of p53 also to regions located distantly from any known p53 target gene. Interestingly, many of these regions possess conserved p53-binding sites and all known hallmarks of enhancer regions. We demonstrate that these p53-bound enhancer regions (p53BERs) indeed contain enhancer activity and interact intrachromosomally with multiple neighboring genes to convey long-distance p53-dependent transcription regulation. Furthermore, p53BERs produce, in a p53-dependent manner, enhancer RNAs (eRNAs) that are required for efficient transcriptional enhancement of interacting target genes and induction of a p53-dependent cell-cycle arrest. Thus, our results ascribe transcription enhancement activity to p53 with the capacity to regulate multiple genes from a single genomic binding site. Moreover, eRNA production from p53BERs is required for efficient p53 transcription enhancement.
authors.affiliation: Division of Gene Regulation, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands; Doctoral Programme in Biomedicine and Experimental Biology, Centre for Neuroscience and Cell Biology, 3004-517 Coimbra, Portugal.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Melo
authors.forename: Jarno
authors.initials: J
authors.lastname: Drost
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Wijchers
authors.forename: Harmen
authors.initials: H
authors.lastname: van de Werken
authors.forename: Elzo
authors.initials: E
authors.lastname: de Wit
authors.forename: Joachim A F
authors.initials: JA
authors.lastname: Oude Vrielink
authors.forename: Ran
authors.initials: R
authors.lastname: Elkon
authors.forename: Sónia A
authors.initials: SA
authors.lastname: Melo
authors.forename: Nicolas
authors.initials: N
authors.lastname: Léveillé
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.forename: Wouter
authors.initials: W
authors.lastname: de Laat
authors.forename: Reuven
authors.initials: R
authors.lastname: Agami
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D002877:Chromosomes, Human / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005796:Genes; D006801:Humans; D061986:MCF-7 Cells; D008957:Models, Genetic; D011485:Protein Binding / Q000235:genetics; D012313:RNA / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022661:RNA, Untranslated / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D002843:Chromatin; D012333:RNA, Messenger; D022661:RNA, Untranslated; D016159:Tumor Suppressor Protein p53; D012313:RNA