title: Integrative genomic analysis reveals widespread enhancer regulation by p53 in response to DNA damage.
abstract: The tumor suppressor p53 has been studied extensively as a direct transcriptional activator of protein-coding genes. Recent studies, however, have shed light on novel regulatory functions of p53 within noncoding regions of the genome. Here, we use a systematic approach that integrates transcriptome-wide expression analysis, genome-wide p53 binding profiles and chromatin state maps to characterize the global regulatory roles of p53 in response to DNA damage. Notably, our approach identified conserved features of the p53 network in both human and mouse primary fibroblast models. In addition to known p53 targets, we identify many previously unappreciated mRNAs and long noncoding RNAs that are regulated by p53. Moreover, we find that p53 binding occurs predominantly within enhancers in both human and mouse model systems. The ability to modulate enhancer activity offers an additional layer of complexity to the p53 network and greatly expands the diversity of genomic elements directly regulated by p53.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Younger
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kenzelmann-Broz
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Heiyoun
authors.initials: H
authors.lastname: Jung
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Attardi
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA John_Rinn@Harvard.edu.
authors.forename: John L
authors.initials: JL
authors.lastname: Rinn
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004249:DNA Damage; D004742:Enhancer Elements, Genetic; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D023281:Genomics; D006801:Humans; D051379:Mice; D011506:Proteins / Q000235:genetics; D062085:RNA, Long Noncoding / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D011506:Proteins; D062085:RNA, Long Noncoding; D016159:Tumor Suppressor Protein p53