Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization

• Published in: Genome research Vol. 24; no. 2; pp. 177 - 184
• Main Authors: Hansen, Kasper D, Sabunciyan, Sarven, Langmead, Ben, Nagy, Noemi, Curley, Rebecca, Klein, Georg, Klein, Eva, Salamon, Daniel, Feinberg, Andrew P
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.02.2014
• Subjects: B-Lymphocytes - pathology; B-Lymphocytes - virology; Carcinogenesis; Cell Transformation, Neoplastic - genetics; Cell Transformation, Viral - genetics; CpG Islands - genetics; DNA Methylation - genetics; DNA, Viral - genetics; Epstein-Barr virus; Genome, Human; Herpesvirus; Herpesvirus 4, Human - genetics; Humans; Medicin och hälsovetenskap; Promoter Regions, Genetic
• ISSN: 1088-9051; 1549-5469; 1549-5469
• DOI: 10.1101/gr.157743.113

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.