Epigenetic Reprogramming by Adenovirus e1a

• Published in: Science (American Association for the Advancement of Science) Vol. 321; no. 5892; pp. 1086 - 1088
• Main Authors: Ferrari, Roberto, Pellegrini, Matteo, Horwitz, Gregory A, Xie, Wei, Berk, Arnold J, Kurdistani, Siavash K
• Format: Journal Article
• Language: English
• Published: Washington, DC American Association for the Advancement of Science 22.08.2008; The American Association for the Advancement of Science
• Subjects: Acetylation; Adenovirus; Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - metabolism; Adenoviruses; Adenoviruses, Human - genetics; Adenoviruses, Human - metabolism; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antivirals; Applied cell therapy and gene therapy; Biological and medical sciences; Cell cycle; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Viral; Cellular biology; CREB-Binding Protein - metabolism; Crk-Associated Substrate Protein - genetics; Crk-Associated Substrate Protein - metabolism; Epigenesis, Genetic; Epigenetics; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetics; Histones; Histones - metabolism; Humans; Individualized Instruction; Medical sciences; Molecular and cellular biology; Mutation; p300-CBP Transcription Factors - metabolism; Promoter regions; Promoter Regions, Genetic; Protein Binding; Proteins; Repression; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Retinoblastoma-Like Protein p107 - genetics; Retinoblastoma-Like Protein p107 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stem cells; Transcription, Genetic; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Viruses; Virus; Cellular reprogramming; Adenoviridae; Epigenetics; Acetylation; Histone; Cell transformation; Carcinogenesis; Vector
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1155546

Adenovirus e1a induces quiescent human cells to replicate. We found that e1a causes global relocalization of the RB (retinoblastoma) proteins (RB, p130, and p107) and p300/CBP histone acetyltransferases on promoters, the effect of which is to restrict the acetylation of histone 3 lysine-18 (H3K18ac) to a limited set of genes, thereby stimulating cell cycling and inhibiting antiviral responses and cellular differentiation. Soon after expression, e1a binds transiently to promoters of cell cycle and growth genes, causing enrichment of p300/CBP, PCAF (p300/CBP-associated factor), and H3K18ac; depletion of RB proteins; and transcriptional activation. e1a also associates transiently with promoters of antiviral genes, causing enrichment for RB, p130, and H4K16ac; increased nucleosome density; and transcriptional repression. At later times, e1a and p107 bind mainly to promoters of development and differentiation genes, repressing transcription. The temporal order of e1a binding requires its interactions with p300/CBP and RB proteins. Our data uncover a defined epigenetic reprogramming leading to cellular transformation.