Large-scale hypomethylated blocks associated with Epstein-Barr virus–induced B-cell immortalization
- Kasper D. Hansen1,2,3,8,
- Sarven Sabunciyan2,4,8,
- Ben Langmead2,5,
- Noemi Nagy6,
- Rebecca Curley2,7,
- Georg Klein6,
- Eva Klein6,
- Daniel Salamon6 and
- Andrew P. Feinberg2,7,9
- 1Department of Biostatistics,
- 2Center for Epigenetics,
- 3Institute of Genetic Medicine,
- 4Department of Pediatrics,
- 5Department of Computer Science, Johns Hopkins University, Baltimore, Maryland 21205, USA;
- 6Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, S-171 77 Stockholm, Sweden;
- 7Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA
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↵8 These authors contributed equally to this work.
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.
Footnotes
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↵9 Corresponding author
E-mail afeinberg{at}jhu.edu
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.157743.113.
Freely available online through the Genome Research Open Access option.
- Received March 15, 2013.
- Accepted September 25, 2013.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.