RT Journal
A1 Hansen, Kasper Daniel
A1 Sabunciyan, Sarven
A1 Langmead, Ben
A1 Nagy, Noemi
A1 Curley, Rebecca
A1 Klein, Georg
A1 Klein, Eva
A1 Salamon, Daniel
A1 Feinberg, Andrew P
T1 Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization
JF Genome Research 
JO Genome Research 
YR 2013 
FD September 25 
DO 10.1101/gr.157743.113 
SP gr.157743.113 
UL http://genome.cshlp.org/content/early/2013/09/25/gr.157743.113.abstract 
AB 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 2/3 of the genome were induced by EBV-immortalization but not by B-cell activation per se. These regions largely corresponded to hypomethylated blocks 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.