The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer.
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.
Fernandez
Agustin F
AF
Cancer Epigenetics Group, Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain.
Rosales
Cecilia
C
Lopez-Nieva
Pilar
P
Graña
Osvaldo
O
Ballestar
Esteban
E
Ropero
Santiago
S
Espada
Jesus
J
Melo
Sonia A
SA
Lujambio
Amaia
A
Fraga
Mario F
MF
Pino
Irene
I
Javierre
Biola
B
Carmona
Francisco J
FJ
Acquadro
Francesco
F
Steenbergen
Renske D M
RD
Snijders
Peter J F
PJ
Meijer
Chris J
CJ
Pineau
Pascal
P
Dejean
Anne
A
Lloveras
Belen
B
Capella
Gabriel
G
Quer
Josep
J
Buti
Maria
M
Esteban
Juan-Ignacio
JI
Allende
Helena
H
Rodriguez-Frias
Francisco
F
Castellsague
Xavier
X
Minarovits
Janos
J
Ponce
Jordi
J
Capello
Daniela
D
Gaidano
Gianluca
G
Cigudosa
Juan Cruz
JC
Gomez-Lopez
Gonzalo
G
Pisano
David G
DG
Valencia
Alfonso
A
Piris
Miguel Angel
MA
Bosch
Francesc X
FX
Cahir-McFarland
Ellen
E
Kieff
Elliott
E
Esteller
Manel
M
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*
D004279:DNA, Viral