Human herpesvirus 6B induces hypomethylation on chromosome 17p13.3 correlating with increased gene expression and virus integration.

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Human herpesvirus 6B induces hypomethylation on chromosome 17p13.3 correlating with increased gene expression and virus integration.

J Virol. 2017 Mar 15;:

Authors: Engdahl E, Dunn N, Niehusmann P, Wideman S, Wipfler P, Becker AJ, Ekström TJ, Almgren M, Fogdell-Hahn A

Abstract
Human herpesvirus 6B (HHV-6B) is a neurotropic beta-herpesvirus that achieves latency by integrating its genome into host cell chromosomes. Several viruses can induce epigenetic modifications in their host cells, but no study has investigated the epigenetic modifications induced by HHV-6B. This study analyzed methylation with Illumina 450K array comparing HHV-6B infected and uninfected Molt-3 T cells three days post infection. Bisulfite pyrosequencing was used to validate Illumina results and investigate methylation over time in vitro Expression of genes was investigated using qPCR, and virus integration was investigated with PCR. A total of 406 CpG sites showed significant HHV-6B induced change in methylation in vitro Remarkably, 86% (351/406) of these CpGs were located <1Mb from chromosomal ends and were all hypomethylated in virus-infected cells. This was most evident at chromosome 17p13.3 where HHV-6B induced CpG hypomethylation already after two days infection, possibly through TET2, which was found upregulated together with an identified cytosine hydroxymethylation. Genes located in the hypomethylated region at 17p13.3 showed significantly upregulated expression in HHV-6B infected cells. A temporal experiment showed HHV-6B integration in Molt-3 cell DNA three days after infection. The telomere at 17p has repeatedly been described as an integration site for HHV-6B and we show for the first time that HHV-6B induces hypomethylation in this region during acute infection, which may play a role in the integration process, possibly by making the DNA more accessible.IMPORTANCE The ability to establish latency in the host is a hallmark of herpesviruses, but mechanisms vary. Human herpesvirus 6B (HHV-6B) is known to establish latency through integration of its genome into the telomeric regions of host cells, with ability to reactivate. Our study is the first to show that HHV-6B specifically induces hypomethylated regions close to the telomeres, and that integrating viruses may use the host methylation machinery to facilitate their integration process. The results from this study contribute to knowledge of HHV-6B biology and virus-host- interaction. This in turn will further progress our understanding of the underlying mechanisms by which HHV-6B contributes to pathological processes and may have important implications in both disease prevention and treatment.

PMID: 28298607 [PubMed - as supplied by publisher]

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