The mechanism by which herpes simplex virus 1 (HSV-1) establishes latency in sensory neurons is largely unknown. Recent studies indicate that epigenetic modifications of the chromatin associated with the latent genome may play a key role in the transcriptional control of lytic genes during latency. In this study, we found both constitutive and facultative types of heterochromatin to be present on the latent HSV-1 genome. Deposition of the facultative marks trimethyl H3K27 and histone variant macroH2A varied at different sites on the genome, whereas the constitutive marker trimethyl H3K9 did not. In addition, we show that in the absence of the latency-associated transcript (LAT), the latent genome shows a dramatic increase in trimethyl H3K27, suggesting that expression of the LAT during latency may act to promote an appropriate heterochromatic state that represses lytic genes but is still poised for reactivation. Due to the presence of the mark trimethyl H3K27, we examined whether Polycomb group proteins, which methylate H3K27, were present on the HSV-1 genome during latency. Our data indicate that Bmi1, a member of the Polycomb repressive complex 1 (PRC1) maintenance complex, associates with specific sites in the genome, with the highest level of enrichment at the LAT enhancer. To our knowledge, these are the first data demonstrating that a virus can repress its gene transcription to enter latency by exploiting the mechanism of Polycomb-mediated repression.After primary infection by herpes simplex virus 1 (HSV-1) in mucosal epithelia, the virus enters sensory neurons, where it can persist as a transcriptionally silent extrachromosomal episome (19). The only abundant transcription that occurs during latency is from a diploid gene in the repeat long segment of the virus that produces the latency-associated transcript (LAT), an 8.3-to 8.5-kb noncoding RNA (20, 21). The LAT is detectably expressed in only one-third of neurons that contain latent HSV genomes (9, 16). Following a reactivation stimulus, some of the latent genomes can exit this state to actively express lytic transcripts and produce new virus. The mechanism by which the genome establishes and maintains this latent state is currently unknown, although it is hypothesized that the reversible nature of the latent phase involves the constant interplay between cellular and viral factors that either keep the viral genome repressed or allow for reactivation.Recent studies have shed light on epigenetic modifications to the HSV-1 genome during the establishment and maintenance of latency. As the genome enters the latent phase in the mouse, an accumulation of the histone mark dimethyl H3 lysine 9 (diMe H3K9), historically known as a transcriptionally repressed marker, is observed on lytic genes, while enrichment of the transcriptionally active histone mark dimethyl H3 lysine 4 (diMe H3K4) decreases (24). Furthermore, once the virus has established latency, the LAT region is enriched in the transcriptionally active marks, acetylated histone H3 lysines 9 and 14 and ...
