c-Myc Represses Transcription of the Epstein-Barr Virus Latent Membrane Protein 1 Early After Primary B Cell Infection

Abstract

Recent evidence has shown that the EBV oncogene LMP1 is not expressed at high levels early after EBV-infection of primary B cells, despite its being essential for the long-term outgrowth of immortalized lymphoblastoid cell lines (LCLs). In this study, we found that expression of LMP1 increased fifty-fold between seven days post infection and the LCL state. Metabolic labeling of nascently transcribed mRNA indicated this was primarily a transcription-mediated event. EBNA2, the key viral transcription factor regulating LMP1, and CTCF, an important chromatin insulator, were recruited to the LMP1 locus similarly early and late after infection. However, the activating histone H3K9Ac mark was enriched at the LMP1 promoter in LCLs relative to early-infected B cells. We found that high c-Myc activity in EBV-infected lymphoma cells as well as overexpression of c-Myc in an LCL model system repressed LMP1 transcription. Finally, we found that chemical inhibition of c-Myc expression both in LCLs and early after primary B-cell infection increased LMP1 expression. These data support a model in which high levels of endogenous c-Myc activity induced early after primary B-cell infection directly represses LMP1 transcription.\n\nIMPORTANCEEBV is a highly successful pathogen that latently infects greater than 90% of adults worldwide and is also causally associated with a number of B-cell malignancies. EBV expresses a set of viral oncoproteins and non-coding RNAs during the latent life cycle with the potential to promote cancer. Critical among these is the viral latent membrane protein, LMP1. Prior work suggests that LMP1 is essential for EBV to immortalize B cells, but our recent work indicates that LMP1 is not produced at high levels during the first few weeks after infection. Here, we show that the transcription of LMP1 can be negatively regulated by a host transcription factor, c-Myc. Ultimately, understanding the regulation of EBV-encoded oncogenes will allow us to better treat cancers that rely on these viral products for survival.