HSV-1 Infection Induces a Downstream Shift of Promoter-Proximal Pausing for Host Genes.

Herpes simplex virus 1 (HSV-1) infection exerts a profound shutoff of host gene expression at multiple levels. Recently, HSV-1 infection was reported to also impact promoter-proximal RNA polymerase II (Pol II) pausing, a key step in the eukaryotic transcription cycle, with decreased and increased Pol II pausing observed for activated and repressed genes, respectively. Here, we demonstrate that HSV-1 infection induces more complex alterations in promoter-proximal pausing than previously suspected for the vast majority of cellular genes. While pausing is generally retained, it is shifted to more downstream and less well-positioned sites for most host genes. The downstream shift of Pol II pausing was established between 1.5 and 3 h of infection, remained stable until at least 6 hours postinfection, and was observed in the absence of ICP22. The shift in Pol II pausing does not result from alternative de novo transcription initiation at downstream sites or read-in transcription originating from disruption of transcription termination of upstream genes. The use of downstream secondary pause sites associated with +1 nucleosomes was previously observed upon negative elongation factor (NELF) depletion. However, downstream shifts of Pol II pausing in HSV-1 infection were much more pronounced than observed upon NELF depletion. Thus, our study reveals a novel aspect in which HSV-1 infection fundamentally reshapes host transcriptional processes, providing new insights into the regulation of promoter-proximal Pol II pausing in eukaryotic cells. IMPORTANCE This study provides a genome-wide analysis of changes in promoter-proximal polymerase II (Pol II) pausing on host genes induced by HSV-1 infection. It shows that standard measures of pausing, i.e., pausing indices, do not properly capture the complex and unsuspected alterations in Pol II pausing occurring in HSV-1 infection. Instead of a reduction of pausing with increased elongation, as suggested by pausing index analysis, HSV-1 infection leads to a shift of pausing to downstream and less well-positioned sites than in uninfected cells for the majority of host genes. Thus, HSV-1 infection fundamentally reshapes a key regulatory step at the beginning of the host transcriptional cycle on a genome-wide scale.

Citation

Elena Weiß, Thomas Hennig, Pilar Graßl, Lara Djakovic, Adam W Whisnant, Christopher S Jürges, Franziska Koller, Michael Kluge, Florian Erhard, Lars Dölken, Caroline C Friedel. HSV-1 Infection Induces a Downstream Shift of Promoter-Proximal Pausing for Host Genes. Journal of virology. 2023 May 31;97(5):e0038123

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PMID: 37093003

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