Widespread activation of antisense transcription of the host genome during herpes simplex virus 1 infection

• Published in: Genome Biology 2017-10, Vol.18 (1), p.209-19, Article 209
• Main Authors: Wyler, Emanuel, Menegatti, Jennifer, Franke, Vedran, Kocks, Christine, Boltengagen, Anastasiya, Hennig, Thomas, Theil, Kathrin, Rutkowski, Andrzej, Ferrai, Carmelo, Baer, Laura, Kermas, Lisa, Friedel, Caroline, Rajewsky, Nikolaus, Akalin, Altuna, Dölken, Lars, Grässer, Friedrich, Landthaler, Markus
• Format: Article
• Language: English
• Subjects: Annotations; Antisense; Antisense RNA; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Binding sites; CRISPR; Fibroblasts; Gene expression; Gene Expression Regulation, Viral - drug effects; Genome, Human; Genomes; Genomics; HeLa Cells; Herpes; Herpes simplex; Herpes Simplex - virology; Herpes viruses; Herpesvirus 1, Human - physiology; Histone Code; Host-Pathogen Interactions - drug effects; Host-Pathogen Interactions - genetics; Humans; ICP4; Infections; Lipopolysaccharides - pharmacology; lncRNA; Metabolism; Monocytes - drug effects; Monocytes - metabolism; NF-kappa B - metabolism; Post-transcription; Promoter Regions, Genetic - genetics; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Reproducibility of Results; RNA polymerase; RNA, Antisense - genetics; RNA, Antisense - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sequence Analysis, RNA; Transcription; Transcription activation; Transcription, Genetic - drug effects; Varicella; Viral Proteins - metabolism; Virus
• ISSN: 1474-760X; 1474-7596; 1474-760X
• DOI: 10.1186/s13059-017-1329-5

Herpesviruses can infect a wide range of animal species. Herpes simplex virus 1 (HSV-1) is one of the eight herpesviruses that can infect humans and is prevalent worldwide. Herpesviruses have evolved multiple ways to adapt the infected cells to their needs, but knowledge about these transcriptional and post-transcriptional modifications is sparse. Here, we show that HSV-1 induces the expression of about 1000 antisense transcripts from the human host cell genome. A subset of these is also activated by the closely related varicella zoster virus. Antisense transcripts originate either at gene promoters or within the gene body, and they show different susceptibility to the inhibition of early and immediate early viral gene expression. Overexpression of the major viral transcription factor ICP4 is sufficient to turn on a subset of antisense transcripts. Histone marks around transcription start sites of HSV-1-induced and constitutively transcribed antisense transcripts are highly similar, indicating that the genetic loci are already poised to transcribe these novel RNAs. Furthermore, an antisense transcript overlapping with the BBC3 gene (also known as PUMA) transcriptionally silences this potent inducer of apoptosis in cis. We show for the first time that a virus induces widespread antisense transcription of the host cell genome. We provide evidence that HSV-1 uses this to downregulate a strong inducer of apoptosis. Our findings open new perspectives on global and specific alterations of host cell transcription by viruses.