Herpesvirus latency is generally thought to be governed by epigenetic 
modifications, but the dynamics of viral chromatin at early timepoints of latent 
infection are poorly understood. Here, we report a comprehensive spatial and 
temporal analysis of DNA methylation and histone modifications during latent 
infection with Kaposi Sarcoma-associated herpesvirus (KSHV), the etiologic agent 
of Kaposi Sarcoma and primary effusion lymphoma (PEL). By use of high resolution 
tiling microarrays in conjunction with immunoprecipitation of methylated DNA 
(MeDIP) or modified histones (chromatin IP, ChIP), our study revealed highly 
distinct landscapes of epigenetic modifications associated with latent KSHV 
infection in several tumor-derived cell lines as well as de novo infected 
endothelial cells. We find that KSHV genomes are subject to profound methylation 
at CpG dinucleotides, leading to the establishment of characteristic global DNA 
methylation patterns. However, such patterns evolve slowly and thus are unlikely 
to control early latency. In contrast, we observed that latency-specific histone 
modification patterns were rapidly established upon a de novo infection. Our 
analysis furthermore demonstrates that such patterns are not characterized by 
the absence of activating histone modifications, as H3K9/K14-ac and H3K4-me3 
marks were prominently detected at several loci, including the promoter of the 
lytic cycle transactivator Rta. While these regions were furthermore largely 
devoid of the constitutive heterochromatin marker H3K9-me3, we observed rapid 
and widespread deposition of H3K27-me3 across latent KSHV genomes, a bivalent 
modification which is able to repress transcription in spite of the simultaneous 
presence of activating marks. Our findings suggest that the modification 
patterns identified here induce a poised state of repression during viral 
latency, which can be rapidly reversed once the lytic cycle is induced.