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

Genome Res. 2014 Feb;24(2):177-84. doi: 10.1101/gr.157743.113. Epub 2013 Sep 25.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • B-Lymphocytes / pathology*
  • B-Lymphocytes / virology
  • Carcinogenesis
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Viral / genetics*
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • DNA, Viral / genetics
  • Genome, Human
  • Herpesvirus 4, Human / genetics*
  • Humans
  • Promoter Regions, Genetic


  • DNA, Viral

Associated data

  • GEO/GSE49629