HSV-1-induced disruption of transcription termination resembles a cellular stress response but selectively increases chromatin accessibility downstream of genes
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Lytic herpes simplex virus 1 (HSV-1) infection triggers disruption of transcription termination (DoTT) of most cellular genes, resulting in extensive intergenic transcription. Similarly, cellular stress responses lead to gene-specific transcription downstream of genes (DoG). In this study, we performed a detailed comparison of DoTT/DoG transcription between HSV-1 infection, salt and heat stress in primary human fibroblasts using 4sU-seq and ATAC-seq. Although DoTT at late times of HSV-1 infection was substantially more prominent than DoG transcription in salt and heat stress, poly(A) read-through due to DoTT/DoG transcription and affected genes were significantly correlated between all three conditions, in particular at earlier times of infection. We speculate that HSV-1 either directly usurps a cellular stress response or disrupts the transcription termination machinery in other ways but with similar consequences. In contrast to previous reports, we found that inhibition of Ca2+ signaling by BAPTA-AM did not specifically inhibit DoG transcription but globally impaired transcription. Most importantly, HSV-1-induced DoTT, but not stress-induced DoG transcription, was accompanied by a strong increase in open chromatin downstream of the affected poly(A) sites. In its extent and kinetics, downstream open chromatin essentially matched the poly(A) read-through transcription. We show that this does not cause but rather requires DoTT as well as high levels of transcription into the genomic regions downstream of genes. This raises intriguing new questions regarding the role of histone repositioning in the wake of RNA Polymerase II passage downstream of impaired poly(A) site recognition.
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Transcriptional read-through can give rise to a chimeric transcript which can be spliced and translated into an aberrant fusion protein, if it invades the downstream gene in a pair of tandem genes.
“Transcriptional read‐through can also give rise to a chimeric transcript which can be spliced and translated into an aberrant fusion protein, if it invades the downstream gene in a pair of tandem genes (Grosso et al, 2015; Hennig et al, 2018).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Hennig et al, 2018
The Introduction and Results report that read-through into a downstream gene produces chimeric transcripts with intergenic splicing between neighboring genes. But the Results section on subcellular RNA localization says these chimeras are retained in the nucleus and are not, or only poorly, translated in HSV-1 infection; it does not establish production of an aberrant fusion protein. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIncreased transcriptional read-through is known to interfere with the expression of downstream genes in other contexts such as cancer or HSV-1 infection in human cells, as well as cold acclimation in plants.
“Increased transcriptional read‐through is known to interfere with the expression of downstream genes also in other contexts such as cancer or HSV‐1 infection in human cells (Grosso et al, 2015; Rutkowski et al, 2015; Hennig et al, 2018), as well as cold acclimation in plants (Kindgren et al, 2018).”
From RNA polymerase II speed: a key player in controlling and adapting transcriptome composition (2021) · cites this paper as Hennig et al, 2018
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- Authors
- Hennig, T., Michalski, M., Rutkowski, A. J., Djakovic, L., Whisnant, A. W., Friedl, M.-S., Jha, B. A., Baptista, M. A. P., L’Hernault, A., Erhard, F., Dölken, L., & Friedel, C. C.
- Affiliations
- University of Würzburg (DE)
- Babraham Institute (GB)
- University of Cambridge (GB)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Dölken, Lars
- Friedel, Caroline C.
- ORCID
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2018-03-26
- Volume
- 14
- Issue
- 3
- Pages
- e1006954
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC5886697
- OpenAlex
- W2791571516
- Cited by
- 95
- References
- 59
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 12 · 2023: 9 · 2022: 16 · 2021: 10 · 2020: 18 · 2019: 7 · 2018: 1
- FWCI
- 3.20
- Type
- journal article
- Language
- en
- Update notices
- new_version (2018-04-05)
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Online Publication Service of Würzburg University (Würzburg University) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (Do1275/2-1, FR2938/7-1)
- H2020 European Research Council (ERC-2016-CoG 721016 - HERPES)
- Alexander von Humboldt-Stiftung
- Auswärtiges Amt
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Epidemiology › Herpesvirus Infections and Treatments
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Keywords
- herpes simplex virus type 1, transcription termination, cellular stress response, salt stress, heat stress, chromatin accessibility, open chromatin, RNA polymerase II, calcium signaling, BAPTA-AM, ATAC-seq, fibroblasts
- MeSH terms
- Cells, Cultured, Chromatin, Fibroblasts, Herpes Simplex, Humans, RNA Polymerase II, Stress, Physiological, Transcription, Genetic, Virus Replication, Gene Expression Regulation, Viral, Herpesvirus 1, Human
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