HSV-1 infection induces a downstream-shift of the +1 nucleosome
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Herpes simplex virus 1 (HSV-1) infection induces a genome-wide loss of host transcriptional activity and widespread disruption of host transcription termination. The latter leads to read-through transcription for thousands of nucleotides beyond poly(A) sites and is associated with induction of open chromatin downstream of genes. In this study, we show that lytic HSV-1 infection alters chromatin accessibility around host promoters resulting in an extension of nucleosome-free regions at transcription start sites into downstream regions. This was most prominent for highly expressed genes and independent of the viral immediate-early proteins ICP0, ICP22, and ICP27 and the virion host shutoff protein vhs. ChIPmentation analysis of the noncanonical histone variant H2A.Z, which is strongly enriched at +1 and -1 nucleosomes, indicated that the downstream extension of accessible chromatin at promoters was linked to a downstream shift of +1 nucleosomes. In yeast, downstream shifts of +1 nucleosomes are induced by RNA Polymerase II (Pol II) degradation. Accordingly, treatment with phosphonoacetic acid (PAA), which inhibits viral DNA replication and alleviates the loss of Pol II from host genes, mostly abolished the downstream shift of +1 nucleosomes in HSV-1 infection. In contrast, irreversible inhibition of Pol II in human cells using α-amanitin similarly altered H2A.Z occupancy and +1 nucleosome positioning as HSV-1 infection. In summary, our study provides strong evidence that HSV-1-induced depletion of Pol II from the host genome leads to a widespread downstream shift of +1 nucleosomes at host gene promoters.
Author summary
Herpes simplex virus 1 (HSV-1) infection leads to a profound shutoff of host transcription during lytic infection. Loss of RNA Polymerase II (Pol II) in yeast has previously been shown to relax +1 nucleosome positioning to more thermodynamically favorable sites downstream of transcription start sites. In this study, we show that a similar phenomenon is likely also at play in lytic HSV-1 infection. Sequencing of accessible chromatin revealed a widening of nucleosome-free regions at host gene promoters into downstream regions. By mapping genome-wide positions of the noncanonical histone variant H2A.Z enriched at +1 and -1 nucleosomes, we demonstrate a downstream shift of +1 nucleosomes for the majority of cellular genes in lytic HSV-1 infection. We confirm that chemical inhibition of Pol II leads to a downstream shift of +1 nucleosomes in human cells. Thus, changes in chromatin architecture at promoters in HSV-1 infection are likely a consequence of HSV-1-induced depletion of Pol II activity from the host genome.
