Systembiologische Analysen zur Abschaltung der Wirtszelle bei Herpes simplex Virus 1 Infektion
Zusammenfassung der Projektergebnisse
Herpes simplex virus 1 (HSV-1) is the causative agent of the common cold sores but is also responsible for severe life-threatening diseases including encephalitis, pneumonia, hepatitis and generalized skin infections. Furthermore, HSV-1 is a paradigm for virus-induced host shutoff exerted at RNA level. Recently, we showed that HSV-1 triggers a widespread disruption of transcription termination (DoTT) of cellular but not viral genes, resulting in extensive readthrough transcription beyond poly(A) sites. Subsequently, similar observations were also reported in cellular stress responses and cancer. We now found that HSV-1-induced DoTT resembles a cellular stress response and leads to nuclear retention of read-through transcripts, thereby contributing to host shut-off. Moreover, we elucidated the molecular mechanism of HSV-1 induced DoTT. Namely, the viral ICP27 protein both disrupts and rescues transcription termination by its interaction with both the PAS complex and viral mRNAs. Within the frame of this project we made the striking observation that HSV-1-induced DoTT, but not stress-induced read-through transcription, was accompanied by an extensive increase in chromatin accessibility downstream of the affected poly(A) sites. These downstream open chromatin regions (dOCRs) extend for tens-of-thousands of nucleotides and essentially match the region of transcription read-through. We hypothesize that HSV-1 selectively impairs histone repositioning in the wake of RNA polymerase II downstream of genes. We have thus established an exciting new model for studying the molecular mechanisms orchestrating gene expression and chromatin architecture in human cells. We will now seek to identify the molecular mechanism responsible for the induction of dOCRs and assess its functional relevance for productive HSV-1 infection.
Projektbezogene Publikationen (Auswahl)
- (2020) Integrative functional genomics decodes herpes simplex virus 1. Nature communications 11 (1) 2038
Whisnant, Adam W.; Jürges, Christopher S.; Hennig, Thomas; Wyler, Emanuel; Prusty, Bhupesh; Rutkowski, Andrzej J.; L'hernault, Anne; Djakovic, Lara; Göbel, Margarete; Döring, Kristina; Menegatti, Jennifer; Antrobus, Robin; Matheson, Nicholas J.; Künzig, F
(Siehe online unter https://doi.org/10.1038/s41467-020-15992-5) - HSV-1-induced disruption of transcription termination resembles a cellular stress response but selectively increases chromatin accessibility downstream of genes. PLOS Pathog. 14, e1006954 (2018)
Hennig T, Michalski M, Rutkowski AJ, Djakovic L, Whisnant AW, Friedl MS, Jha BA, Baptista MAP, L'Hernault A, Erhard F, Dölken L, Friedel CC
(Siehe online unter https://doi.org/10.1371/journal.ppat.1006954)
