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

Abstract

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 function as transcriptional enhancers and promoters when this repression is lost. Epstein-Barr virus (EBV), which transforms primary B cells into continuously proliferating cells, is a tumor virus associated with lymphomas. We report here that transformation of primary B cells by EBV leads to genome-wide activation of LTR enhancers and promoters. The activation of LTRs coincides with local DNA hypomethylation and binding by transcription factors such as RUNX3, EBF1, and EBNA2. The set of activated LTRs is unique to transformed B cells compared with other cell lines known to have activated LTRs. Furthermore, we found that LTR activation impacts the B cell transcriptome by up-regulating transcripts driven by cryptic LTR promoters. These transcripts include genes important to oncogenesis of Hodgkin lymphoma and other cancers, such as HUWE1/HECTH9. These data suggest that the activation of LTRs by EBV-induced transformation is 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.

APOBEC‐mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV‐positive gastric cancer

“…The mechanisms of tumorigenesis so far described for EBVinduced tumors include the interference of EBV with cell-cycle checkpoints (G1 as well as G2/M transitions and the assembly of the mitotic spindle), the inactivation of cell death pathways, when immortalized EBV-infected B-cells proliferate in a central neoplastic mechanism of B-cell lymphomas 27 as well as the genome-wide reactivation of enhancers and promoters located near cryptic and otherwise repressed long terminal repeats of inactive human endogenous retroviruses. 28 In these cells, EBV-infection acts as a somatic mutator, leading to the activation of AID, an enzyme that mediates class switch recombination of immunoglobulin genes and induces cytosine deamination and somatic hypermutation. 29 These findings indicate that AID has a role in EBV-induced lymphomagenesis in B cells.…”

Expression of A New Endogenous Retrovirus-Associated Transcript in Hodgkin Lymphoma Cells

“…By qRT-PCR, high levels of THOLE were only detectable in L-1236 cells and not in other samples (Figure 2). Interestingly, other LTR8 sequences have been shown to be activated by Epstein-Barr virus (EBV) [26]. All HL cell lines analyzed in our study are EBV negative.…”

APOBEC-mediated DNA alterations: a possible new mechanism of carcinogenesis in EBV-positive gastric cancer

“…The mechanisms of tumorigenesis so far described for EBV-induced tumors include the interference of EBV with cell-cycle checkpoints (G1 as well as G2/M transitions and the assembly of the mitotic spindle), the inactivation of cell death pathways, when immortalized EBV-infected B-cells proliferate in a central neoplastic mechanism of B-cell lymphomas [15] as well as the genome-wide reactivation of enhancers and promoters located near cryptic and otherwise repressed long terminal repeats of inactive human endogenous retroviruses [16]. In these cells, EBV-infection acts as a somatic mutator, leading to the activation of AID, an enzyme that mediates class switch recombination of immunoglobulin genes and induces cytosine deamination and somatic hypermutation [17].…”