Viruses manipulate cellular CpG DNA methylation and transposable elements

Kaposi’s sarcoma associated herpesvirus (KSHV, HHV-8) is a gamma herpesvirus associated with several human malignancies, such as Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease (MCD). DNA methylation at CpG dinucleotides is an epigenetic mark dysregulated in many cancer types, but little is known about the impact of KSHV on the human genome. We performed a comprehensive CpG methylation analysis of the human methylome in KSHV-infected cells and KSHV-associated malignancies. This analysis revealed initial hyper-methylation following infection, and progressive hypo-methylation towards transformation. The tight connection between CpG methylation and repression of transposable elements (TEs) prompted us test how viral infection modulates the expression of human TEs. Transposable elements, as their name suggest, have the ability to transpose (jump) within their host genome. They are ubiquitous in eukaryotic genomes, occupying about 45% of the human genome. Transcriptome analysis in KSHV infected cells revealed up-regulation of many TEs, including LTR human endogenous retro-viruses (HERVs) and non-LTR Long Interspersed Element -1 (LINE-1). Further analysis detected dramatic loss of methylation in the promoters of these TEs in KSHV infected cells. In addition, we present novel fused long non-coding RNA (lncRNA) between TEs and cellular transcripts that are critical for KSHV viral latency.