title: A p53-bound enhancer region controls a long intergenic noncoding RNA required for p53 stress response.
abstract: Genome-wide chromatin studies identified the tumor suppressor p53 as both a promoter and an enhancer-binding transcription factor. As an enhancer factor, p53 can induce local production of enhancer RNAs, as well as transcriptional activation of distal neighboring genes. Beyond the regulation of protein-coding genes, p53 has the capacity to regulate long intergenic noncoding RNA molecules (lincRNAs); however, their importance to the p53 tumor suppressive function remains poorly characterized. Here, we identified and characterized a novel p53-bound intronic enhancer that controls the expression of its host, the lincRNA00475 (linc-475). We demonstrate the requirement of linc-475 for the proper induction of a p53-dependent cell cycle inhibitory response. We further confirm the functional importance of linc-475 in the maintenance of CDKN1A/p21 levels, a cell cycle inhibitor and a major p53 target gene, following p53 activation. Interestingly, loss of linc-475 reduced the binding of both p53 and RNA polymerase II (RNAPII) to the promoter of p21, attenuating its transcription rate following p53 activation. Altogether, our data suggest a direct role of p53-bound enhancer domains in the activation of lincRNAs required for an efficient p53 transcriptional response.
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: C A
authors.initials: CA
authors.lastname: Melo
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Léveillé
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Rooijers
authors.affiliation: Hubrecht Institute-KNAW and University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Wijchers
authors.affiliation: Hubrecht Institute-KNAW and University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Geeven
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Tal
authors.affiliation: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Institute of Pathology and Molecular Immunology of the University of Porto (IPATIMUP), Porto, Portugal.
authors.forename: S A
authors.initials: SA
authors.lastname: Melo
authors.affiliation: Hubrecht Institute-KNAW and University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: de Laat
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Genetics, Erasmus MC, Rotterdam University, Rotterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Agami
mesh_terms: D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
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; D012319:RNA Polymerase II