Funktionelle Analyse der Induktion offenen Chromatins stromabwärts von Genen in der HSV-1-Infektion
Zusammenfassung der Projektergebnisse
Herpes simplex virus 1 (HSV-1) is the causative agent of the common cold sores but also responsible for severe, life-threatening diseases including encephalitis, pneumonia, hepatitis and generalized skin infections. HSV-1 is a paradigm for virus-induced host shut-off exerted at RNA level. Previously, we identified that the HSV-1 immediate early protein ICP27 triggers widespread disruption of termination (DoTT) of RNA polymerase II (Pol II) transcription during lytic infection. Interestingly, a virus-induced stress response and stress-induced disruption of transcription termination contributes to the excessive transcription downstream of genes observed in lytic HSV-1 infection. HSV-1- but not stress-induced poly(A) read-through transcription is accompanied by a dramatic increase in chromatin accessibility downstream of the affected poly(A) signals. In the frame of this project, which combines both wet-lab and integrative bioinformatic analyses, we showed that the viral immediate early protein ICP22 is both necessary and sufficient for the induction of downstream open chromatin regions (dOCRs) upon disruption of transcription termination. This was matched by a marked ICP22-dependent loss of histones downstream of affected genes consistent with impaired histone repositioning in the wake of Pol II. Efficient knock-down of the ICP22-interacting histone chaperon FACT was not sufficient to induce dOCRs in ∆ICP22 infection but increased dOCR induction in wild-type HSV-1 infection. Interestingly, this was accompanied by a marked increase in chromatin accessibility within gene bodies. We propose a model in which allosteric changes in Pol II composition downstream of genes and ICP22-mediated interference with FACT activity explain the differential impairment of histone repositioning downstream of genes in the wake of Pol II observed in HSV-1 infection. While the functional relevance of dOCR induction during lytic infection remains unclear, we hypothesize that it may play an important role in virus reactivation from latency.
Projektbezogene Publikationen (Auswahl)
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A Review of the Multipronged Attack of Herpes Simplex Virus 1 on the Host Transcriptional Machinery. Viruses, 13(9), 1836.
Hennig, Thomas; Djakovic, Lara; Dölken, Lars & Whisnant, Adam W.
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The HSV-1 ICP22 protein selectively impairs histone repositioning upon Pol II transcription downstream of genes. Springer Science and Business Media LLC.
Djakovic, Lara; Hennig, Thomas; Reinisch, Katharina; Milic, Andrea; Whisnant, Adam; Wolf, Katharina; Weiß, Elena; Haas, Tobias; Grothey, Arnhild; Juerges, Christopher; Kluge, Michael; Wolf, Elmar; Erhard, Florian; Friedel, Caroline & Dolken, Lars
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CDK11 regulates pre-mRNA splicing by phosphorylation of SF3B1. Nature, 609(7928), 829-834.
Hluchý, Milan; Gajdušková, Pavla; Ruiz, de los Mozos Igor; Rájecký, Michal; Kluge, Michael; Berger, Benedict-Tilman; Slabá, Zuzana; Potěšil, David; Weiß, Elena; Ule, Jernej; Zdráhal, Zbyněk; Knapp, Stefan; Paruch, Kamil; Friedel, Caroline C. & Blazek, Dalibor
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HSV-1 infection induces a downstream shift of promoter-proximal pausing for most host genes. Cold Spring Harbor Laboratory.
Weiß, Elena; Hennig, Thomas; Graßl, Pilar; Djakovic, Lara; Whisnant, Adam W.; Jürges, Christopher S.; Koller, Franziska; Kluge, Michael; Erhard, Florian; Dölken, Lars & Friedel, Caroline C.
