title: Genome-wide analysis of p53-regulated transcription in Myc-driven lymphomas.
abstract: The tumour suppressor p53 is a transcription factor that controls cellular stress responses. Here, we dissected the transcriptional programmes triggered upon restoration of p53 in Myc-driven lymphomas, based on the integrated analysis of p53 genomic occupancy and gene regulation. p53 binding sites were identified at promoters and enhancers, both characterized by the pre-existence of active chromatin marks. Only a small fraction of these sites showed the 20 base-pair p53 consensus motif, suggesting that p53 recruitment to genomic DNA was primarily mediated through protein-protein interactions in a chromatin context. p53 also targeted distal sites devoid of activation marks, at which binding was prevalently driven by sequence recognition. In all instances, the relevant motif was the canonical unsplit consensus element, with no clear evidence for p53 recruitment by split motifs. At promoters, p53 binding to the consensus motif was associated with gene induction, but not repression, indicating that the latter was most likely indirect. Altogether, our data highlight key features of genome recognition by p53 and provide unprecedented insight into the pathways associated with p53 reactivation and tumour regression, paving the way for their therapeutic application.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: C
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: M 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: A
authors.initials: A
authors.lastname: Sabò
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Verrecchia
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rotta
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: T
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: S
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Milan, Italy.
authors.forename: S
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: B
authors.initials: B
authors.lastname: Amati
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000502:physiology*; D055106:Genome-Wide Association Study; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53