Epstein-Barr Virus (EBV) is perhaps most famous as the “kissing disease” and the cause of infectious mononucleosis outbreaks in school-aged children. Even if you didn’t experience the weeks-long exhaustion associated with mono, chances are you’ve been infected: over 90% of adults been exposed to the virus. While not everyone experiences the symptoms of mono when they are infected, lifelong EBV infection due to latency has a more ominous aspect, as EBV infection is associated with 100,000-200,000 annual cancer cases worldwide.
EBV infects B cells and epithelial cells, and causes life-long infection with viral DNA through one of three latency programs. These latent infections can cause immortalization of the host cells, creating a favorable environment for additional accumulation of cancer-related mutations. People without healthy immune systems can be prone to EBV-associated lymphomas, which are most commonly associated with expression of latent viral genes that have oncogenic properties. But people with healthy immune systems can also be susceptible to EBV-driven cancers, but without expression of these oncogenic viral genes. How could viral infection promote oncogenesis in these cells?
New research from the Journal of Virology suggests the mechanism may involve noncoding regions of the viral RNA. The transcripts start near a BamHI restriction enzyme recognition sequence in the viral genome and are directionally transcribed, giving them the name BamH1 A Rightward Transcripts, or BARTs. While the BARTs do contain some open reading frames, they also contain sequence to produce 44 miRNAs – the same miRNAs found in tumors that contain the EBV BARTs. BART-derived miRNAs can modify host cell gene expression patterns; could that be a function of the longer BART RNAs too?
This hypothesis was tested by Marquitz et. al. through RNA-seq of cells expressing a full-length BART cDNA but no other EBV genes. The data revealed many cellular pathways were affected, including regulation of anchorage-independent growth and cell cycle. EBV increased expression of the oncogene myc and decreased expression of the cell-cycle checkpoint gene Rb. This suggests the miRNAs may play a role in transformation of normal (non-oncogenic) cells into oncogenic cells. The data also suggest that the BARTs not only generate miRNAs but also act in the full-length BART form as a long noncoding RNA (lncRNA).
What are lncRNAs? Long non-coding RNAs are transcribed pieces of RNA that are over 200 nucleotides long and don’t generate a protein product. There are thought to be as many lncRNAs as there are open reading frames in the human genome. The function for many of the lncRNAs isn’t known, although they can recruit transcription factors or chromatin remodeling enzymes to alter transcriptional or chomatin state.
This new research shows that viral lncRNAs can also change the cell’s transcriptional pattern, likely using the same mechanisms as human lncRNAs – although the exact mechanism has yet to be revealed. With this study, we are a bit closer to understanding how EBV transforms normal cells without production of its oncogenic viral proteins.
-- Julie Wolf