Abstract
BackgroundHerpesviruses 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.ResultsHere, 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.ConclusionsWe 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.
Highlights
Herpesviruses can infect a wide range of animal species
Transcripts were categorized as divergent, convergent, or internal antisense transcripts (Fig. 1d), or, if the transcription start site (TSS) of the antisense transcript was not within 10 kb of a TSS of a transcript on the opposite strand, and if it did not overlap a gene body, it was categorized as “undefined”
Overexpression of ICP4 is sufficient for induction of some antisense transcripts Because some antisense transcripts were not detectable in cells infected with the ΔICP4 virus (Fig. 3c), we investigated whether ICP4 itself is sufficient to induce some antisense transcripts
Summary
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 are a family of enveloped DNA viruses which can infect a wide range of animal species. Transcription outside of annotated genes, sometimes called “pervasive transcription”, has attracted increasing interest in the past years [9, 10]. This term describes transcription from loci not immediately adjacent to known genes, giving rise to long non-coding RNAs (lncRNAs) or enhancer-derived RNAs (eRNAs). We focus on the second and third categories, which we subsume for clarity of presentation as “antisense transcripts” in our text
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