Epstein–Barr virus-mediated transformation of B cells induces global chromatin changes independent to the acquisition of proliferation

Hernando, Henar; Islam, Abul, 1978-; Rodríguez Ubreva, Javier; Forné, Ignasi; Ciudad, Laura; Imhof, Axel; Shannon Lowe, Claire; Ballestar, Esteban

doi:http://dx.doi.org/10.1093/nar/gkt886

Epstein–Barr virus-mediated transformation of B cells induces global chromatin changes independent to the acquisition of proliferation

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Citació

Hernando H, Islam ABMMK, Rodríguez-Ubreva J, Forné I, Ciudad L, Imhof A, et al. Epstein–Barr virus-mediated transformation of B cells induces global chromatin changes independent to the acquisition of proliferation. Nucleic Acids Research. 2014 Jan 1;42(1):249-63. DOI: 10.1093/nar/gkt886

Resum

Epstein–Barr virus (EBV) infects and transforms human primary B cells inducing indefinite proliferation. To investigate the potential participation of chromatin mechanisms during the EBV-mediated transformation of resting B cells we performed an analysis of global changes in histone modifications. We observed a remarkable decrease and redistribution of heterochromatin marks including H4K20me3, H3K27me3 and H3K9me3. Loss of H4K20me3 and H3K9me3 occurred at constitutive heterochromatin repeats. For H3K27me3 and H3K9me3, comparison of ChIP-seq data revealed a decrease in these marks in thousands of genes, including clusters of HOX and ZNF genes, respectively. Moreover, DNase-seq data comparison between resting and EBV-transformed B cells revealed increased endonuclease accessibility in thousands of genomic sites. We observed that both loss of H3K27me3 and increased accessibility are associated with transcriptional activation. These changes only occurred in B cells transformed with EBV and not in those stimulated to proliferate with CD40L/IL-4, despite their similarities in the cell pathways involved and proliferation rates. In fact, B cells infected with EBNA-2 deficient EBV, which have much lower proliferation rates, displayed similar decreases for heterochromatic histone marks. Our study describes a novel phenomenon related to transformation of B cells, and highlights its independence of the pure acquisition of proliferation.