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

Kasper Daniel Hansen, Sarven Sabunciyan, Ben Langmead, Noemi Nagy, Rebecca Curley, Georg Klein, Eva Klein, Daniel Salamon, Andrew P Feinberg

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)177-184
Number of pages8
JournalGenome Research
Volume24
Issue number2
DOIs
StatePublished - Feb 2014

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Human Herpesvirus 4
B-Lymphocytes
DNA Methylation
Neoplasms
Genome
CpG Islands
Herpesviridae
Epigenomics
Methylation
Lymphoma
Carcinogenesis
Cell Culture Techniques
Gene Expression

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization. / Hansen, Kasper Daniel; Sabunciyan, Sarven; Langmead, Ben; Nagy, Noemi; Curley, Rebecca; Klein, Georg; Klein, Eva; Salamon, Daniel; Feinberg, Andrew P.

In: Genome Research, Vol. 24, No. 2, 02.2014, p. 177-184.

Research output: Contribution to journalArticle

Hansen, Kasper Daniel ; Sabunciyan, Sarven ; Langmead, Ben ; Nagy, Noemi ; Curley, Rebecca ; Klein, Georg ; Klein, Eva ; Salamon, Daniel ; Feinberg, Andrew P. / Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization. In: Genome Research. 2014 ; Vol. 24, No. 2. pp. 177-184.
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