title: Genome-wide analysis of p53 transcriptional programs in B cells upon exposure to genotoxic stress in vivo.
abstract: The tumor suppressor p53 is a transcription factor that coordinates the cellular response to DNA damage. Here we provide an integrated analysis of p53 genomic occupancy and p53-dependent gene regulation in the splenic B and non-B cell compartments of mice exposed to whole-body ionizing radiation, providing insight into general principles of p53 activity in vivo. In unstressed conditions, p53 bound few genomic targets; induction of p53 by ionizing radiation increased the number of p53 bound sites, leading to highly overlapping profiles in the different cell types. Comparison of these profiles with chromatin features in unstressed B cells revealed that, upon activation, p53 localized at active promoters, distal enhancers, and a smaller set of unmarked distal regions. At promoters, recognition of the canonical p53 motif as well as binding strength were associated with p53-dependent transcriptional activation, but not repression, indicating that the latter was most likely indirect. p53-activated targets constituted the core of a cell type-independent response, superimposed onto a cell type-specific program. Core response genes included most of the known p53-regulated genes, as well as many new ones. Our data represent a unique characterization of the p53-regulated response to ionizing radiation in vivo.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tonelli
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Morelli
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Rotta
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: Thelma
authors.initials: T
authors.lastname: Capra
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Sabò
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Campaner
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.|Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D001665:Binding Sites; D002478:Cells, Cultured; D004249:DNA Damage; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000528:radiation effects; D055106:Genome-Wide Association Study; D005838:Genotype; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014916:Whole-Body Irradiation
chemical_list: D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53
keywords: B cells; DNA damage; chromatin; p53; transcription