Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization.
Altered DNA methylation occurs ubiquitously in human cancer from the earliest measurable stages. A cogent approach to understanding the mechanism and timing of altered DNA methylation is to analyze it in the context of carcinogenesis by a defined agent. Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with lymphoma and nasopharyngeal carcinoma, but also used commonly in the laboratory to immortalize human B-cells in culture. Here we have performed whole-genome bisulfite sequencing of normal B-cells, activated B-cells, and EBV-immortalized B-cells from the same three individuals, in order to identify the impact of transformation on the methylome. Surprisingly, large-scale hypomethylated blocks comprising two-thirds of the genome were induced by EBV immortalization but not by B-cell activation per se. These regions largely corresponded to hypomethylated blocks that we have observed in human cancer, and they were associated with gene-expression hypervariability, similar to human cancer, and consistent with a model of epigenomic change promoting tumor cell heterogeneity. We also describe small-scale changes in DNA methylation near CpG islands. These results suggest that methylation disruption is an early and critical step in malignant transformation.
Department of Biostatistics.
Kasper D
KD
Hansen
Sarven
S
Sabunciyan
Ben
B
Langmead
Noemi
N
Nagy
Rebecca
R
Curley
Georg
G
Klein
Eva
E
Klein
Daniel
D
Salamon
Andrew P
AP
Feinberg
D001402:B-Lymphocytes / Q000473:pathology* / Q000821:virology; D063646:Carcinogenesis; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002472:Cell Transformation, Viral / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics; D015894:Genome, Human; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic
D004279:DNA, Viral