HHV-6B induces telomeric hypomethylation, possibly facilitating integration

A study led by Anna-Fogdell Hahn of Karolinska Institutet determined that HHV-6B induces unique, region-specific DNA hypomethylation in host cells within 3 days of active infection, which corresponds to increased gene expression and viral integration. The authors propose that the epigenetic modification may facilitate HHV-6B integration.

Elin Enghdahl, PhD and Anna Fogdell-Hahn of Karolinska Institute

Elin Enghdahl, PhD and Anna Fogdell-Hahn of Karolinska Institute

The vast majority of the hypomethyation occurred near telomeres, and the changes were most evident at 17p13.3, a known site of HHV-6 integration. Active demethylation usually involves the TET enzymes, and TET2 expression was significantly up-regulated by HHV-6B in the T-cells analyzed, indicating a role in the de-methylation process. This near-telomeric region at 17p13.3 contains the genes RPH3AL, RFLNB, VPS53, and DOC2B, all which displayed increased expression. In addition, the study suggested that HHV-6B integration into the 17p telomere also occurred during this time period.

An earlier study found that the histone deacetylase inhibitor Trichostatin A reactivated HHV-6A from latent integration (Arbuckle 2010). Histone acetylation is similar to DNA hypomethylation in that it leads to a more relaxed DNA structure and increased gene transcription.

The authors note that viruses have evolved strategies to alter host epigenetic machinery for their own survival, latent virus DNA is heavily methylated and thus protected from immune detection, but the viruses retain the ability to become hypomethylated resulting in activation (Arvey 2013). Viruses can also encode proteins that interact with epigenetic modulators, which may repress expression of immune response genes, with severe implications for the host cell. For example, EBV infection induces increased DNA methylation and reduced expression of many host cell genes resulting in cancer (Matsusaka 2011).

As hypomethylation of sub-telomeric DNA has been associated with increased telomere recombination frequencies, and telomeres with integrated HHV-6A/B have previously been shown to be unstable, it is conceivable that the telomeric instability associated with HHV-6B integration at this site could contribute to improper cell-cycle activity, and possibly cancer. HHV-6 has been implicated in a variety of cancers. 17p13.3 contains a tumor suppressor gene that is under-expressed or exhibits loss of heterozygosity in some cancers (Zheng 2012).HHV-6B has been associated with gastrointestinal cancers (Halme 2013, Sultanova 2013), and 17p13.3 has recently been identified as a locus associated with colorectal cancer (Zhang 2014).

“The findings add to our understanding of HHV-6 integration and latency”, commented first author Elin Engdahl, PhD. “We hope that further studies may help to identify therapeutic targets to limit HHV-6 integration or reactivation.”

Find the full paper here: Engdahl 2017