Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
Institute of Virology, Saarland University Medical School, Kirrbergerstrasse, Haus 47, 66421, Homburg/Saar, Germany.
Genome Biol. 2017 Oct 31;18(1):209. 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.
疱疹病毒可以感染广泛的动物物种。单纯疱疹病毒 1（HSV-1）是可以感染人类的八种疱疹病毒之一，在全球范围内广泛流行。疱疹病毒已经进化出多种方式来使受感染的细胞适应其需要，但关于这些转录和转录后修饰的知识还很匮乏。
在这里，我们表明 HSV-1 诱导大约 1000 个来自人类宿主细胞基因组的反义转录本的表达。这些反义转录本中的一部分也被密切相关的水痘带状疱疹病毒激活。反义转录本起源于基因启动子或基因体内，它们对早期和立即早期病毒基因表达的抑制具有不同的敏感性。主要病毒转录因子 ICP4 的过表达足以激活一部分反义转录本。HSV-1 诱导的和组成型转录的反义转录本周围的组蛋白标记高度相似，表明这些新的 RNA 已经准备好转录。此外，与 BBC3 基因（也称为 PUMA）重叠的反义转录本在顺式转录上沉默了这种有效的凋亡诱导剂。
我们首次表明病毒会诱导宿主细胞基因组的广泛反义转录。我们提供的证据表明，HSV-1 利用这一点来下调一种强烈的凋亡诱导剂。我们的发现为病毒对宿主细胞转录的全局和特定改变开辟了新的视角。
