Many breakthroughs in cancer immunotherapy have ultimately come from learning how chronic infections interact with the immune system and how cancer cells, in turn, learn to mimic some of the same traits associated with chronically infected cells. Thanks to recent advances in Next Generation Sequencing, among other techniques, heterochromatic DNA - previously considered to be genomic “dark matter” - was found to be transcriptionally active in cancer cells. In particular, it has been found that tumors express a family of satellite RNA that are typically silent in healthy cells. Such RNA often emanate from pericentromeric regions and display a class of CpG nucleic acid motifs that are rarely found in the human genome, but may be present in zoonotic viruses or bacteria and may trigger the pattern recognition receptors of the innate immune system which detect “non-self” material. The human satellite RNA HSATII is an outlier even within this group, as it displays CpG motifs at unusually high density and is overexpressed in tumors.
The complexity of changes observed in cancer cells and infected cells is profound and there are many biological processes commonly manipulated in these pathogenic settings. As we were specifically interested in aspects of host-pathogen interactions that tumor’s mimic, we wondered if chronic viruses could change infected cells transcriptionally, in similar way to cancer, by inducing HSATII RNA. We not only discovered that this satellite repeat RNA is strongly overexpressed by some members of herpesvirus family (HCMV, HSV) and regulated by viral proteins, but we found that its expression is advantageous for viral replication and modulates cellular behavior that can aid to viral pathogenesis.
Our virus-centered studies not only uncovered interesting aspects of viral infection adding another piece to growing speculations about HCMV oncomodulatory effects, but also provided an inducible system that could accelerate investigations about possible roles HSATII RNA plays in many other diseases. Clearly it implies the possibility of novel therapeutic approaches to treat both conditions. Moreover, both the induction of repetitive elements and the inflammation associated with chronic inflection has been implicated in a range of diseases over the past year. For instance, Alzheimer’s disease has been associated with HSV infection, and the movement of repeats has been associated with loss of epigenetic control during aging. It is possible that work such as ours could provide a mechanistic bridge for these provocative associations.
Poster: HCMV infection induces HSATII expression. HSATII RNA was visualized in mock- and HCMV-infected human fibroblasts at 24 hpi using an in situ hybridization assay. Nuclei were counterstained with hematoxylin (light blue) and HSATII RNA was detected with a labeled probe (red).