Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization
- Kasper Daniel Hansen1,
- Sarven Sabunciyan1,
- Ben Langmead1,
- Noemi Nagy2,
- Rebecca Curley1,
- Georg Klein2,
- Eva Klein2,
- Daniel Salamon2 and
- Andrew P Feinberg1,3
- ↵* Corresponding author; email: afeinberg{at}jhu.edu
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 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.
- Received March 15, 2013.
- Accepted September 25, 2013.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
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/.
