title: The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer.
abstract: The natural history of cancers associated with virus exposure is intriguing, since only a minority of human tissues infected with these viruses inevitably progress to cancer. However, the molecular reasons why the infection is controlled or instead progresses to subsequent stages of tumorigenesis are largely unknown. In this article, we provide the first complete DNA methylomes of double-stranded DNA viruses associated with human cancer that might provide important clues to help us understand the described process. Using bisulfite genomic sequencing of multiple clones, we have obtained the DNA methylation status of every CpG dinucleotide in the genome of the Human Papilloma Viruses 16 and 18 and Human Hepatitis B Virus, and in all the transcription start sites of the Epstein-Barr Virus. These viruses are associated with infectious diseases (such as hepatitis B and infectious mononucleosis) and the development of human tumors (cervical, hepatic, and nasopharyngeal cancers, and lymphoma), and are responsible for 1 million deaths worldwide every year. The DNA methylomes presented provide evidence of the dynamic nature of the epigenome in contrast to the genome. We observed that the DNA methylome of these viruses evolves from an unmethylated to a highly methylated genome in association with the progression of the disease, from asymptomatic healthy carriers, through chronically infected tissues and pre-malignant lesions, to the full-blown invasive tumor. The observed DNA methylation changes have a major functional impact on the biological behavior of the viruses.
authors.affiliation: Cancer Epigenetics Group, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain.
authors.forename: Agustin F
authors.initials: AF
authors.lastname: Fernandez
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rosales
authors.forename: Pilar
authors.initials: P
authors.lastname: Lopez-Nieva
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Graña
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.forename: Santiago
authors.initials: S
authors.lastname: Ropero
authors.forename: Jesus
authors.initials: J
authors.lastname: Espada
authors.forename: Sonia A
authors.initials: SA
authors.lastname: Melo
authors.forename: Amaia
authors.initials: A
authors.lastname: Lujambio
authors.forename: Mario F
authors.initials: MF
authors.lastname: Fraga
authors.forename: Irene
authors.initials: I
authors.lastname: Pino
authors.forename: Biola
authors.initials: B
authors.lastname: Javierre
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Carmona
authors.forename: Francesco
authors.initials: F
authors.lastname: Acquadro
authors.forename: Renske D M
authors.initials: RD
authors.lastname: Steenbergen
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Meijer
authors.forename: Pascal
authors.initials: P
authors.lastname: Pineau
authors.forename: Anne
authors.initials: A
authors.lastname: Dejean
authors.forename: Belen
authors.initials: B
authors.lastname: Lloveras
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capella
authors.forename: Josep
authors.initials: J
authors.lastname: Quer
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.forename: Juan-Ignacio
authors.initials: JI
authors.lastname: Esteban
authors.forename: Helena
authors.initials: H
authors.lastname: Allende
authors.forename: Francisco
authors.initials: F
authors.lastname: Rodriguez-Frias
authors.forename: Xavier
authors.initials: X
authors.lastname: Castellsague
authors.forename: Janos
authors.initials: J
authors.lastname: Minarovits
authors.forename: Jordi
authors.initials: J
authors.lastname: Ponce
authors.forename: Daniela
authors.initials: D
authors.lastname: Capello
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Juan Cruz
authors.initials: JC
authors.lastname: Cigudosa
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gomez-Lopez
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Piris
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Bosch
authors.forename: Ellen
authors.initials: E
authors.lastname: Cahir-McFarland
authors.forename: Elliott
authors.initials: E
authors.lastname: Kieff
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D002472:Cell Transformation, Viral / Q000235:genetics; D002478:Cells, Cultured; D002874:Chromosome Mapping; D019175:DNA Methylation / Q000502:physiology; D004267:DNA Viruses / Q000235:genetics* / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics / Q000378:metabolism; D005260:Female; D016679:Genome, Viral; D006367:HeLa Cells; D006515:Hepatitis B virus / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000235:genetics; D052162:Human papillomavirus 16 / Q000235:genetics; D052161:Human papillomavirus 18 / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000821:virology*
chemical_list: D004279:DNA, Viral