LTRs activated by Epstein-Barr virus–induced transformation of B cells alter the transcriptome

Endogenous retroviruses (ERVs) are ancient viral elements that have accumulated in the genome through retrotransposition events. Although they have lost their ability to transpose, many of the long terminal repeats (LTRs) that originally flanked full-length ERVs, maintain the ability to regulate transcription. While these elements are typically repressed in somatic cells, they can regulate proximal transcripts when this repression is diminished. It has become clear in recent years that a subset of LTR promoters are activated during pathological conditions, including cancer. However, the events driving LTR activation are not well understood. Epstein-Barr virus (EBV), which transforms primary B cells into continuously proliferating cells, is a tumor virus first associated with lymphomas. We report here that transformation of primary B cells by EBV leads to genome-wide activation of LTR promoters. The activation of LTRs coincides with local DNA hypomethylation and binding by transcription factors such as RUNX3, EBF1, and EBNA2. The set of EBV-activated LTRs is unique to transformed B cells when compared to cell lines known to upregulate LTRs. Furthermore, we found that EBV-induced LTR activation impacts the B cell transcriptome by upregulating >100 coding and non-coding transcripts. These transcripts include isoforms of CSF1R and IRF5, which are both important to oncogenesis of Hodgkin lymphoma. These data suggest that the activation of LTRs by EBV may be important to the pathology of EBV-associated cancers. Altogether, our results indicate that EBV-induced transformation of B cells alters endogenous retroviral element activity, thereby impacting host gene regulatory networks and oncogenic potential.