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The Epigenetic Landscape of Latent Kaposi Sarcoma-Associated Herpesvirus Genomes

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PLoS Pathogens

Public Library of Science

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      Abstract

      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.

      Author Summary

      A characteristic feature of herpesviruses is their ability to establish a latent infection during which most of the viral genes are silenced. As a consequence, no viral progeny is produced and the host cell remains viable. While the viral genome may persist in the nucleus of such cells indefinitely, it retains the ability to re-enter the lytic cycle and produce new virions if conditions in the cell become unfavorable. The molecular requirements for the establishment of latency are poorly understood, but are thought to depend on epigenetic modifications of the viral episome. Here, we report a genome-wide screen to investigate DNA methylation and histone modification patterns associated with latent infection by Kaposi Sarcoma-associated herpesvirus (KSHV), a tumor virus linked to the development of several cancers. We find that latency is likely to be determined by modifications commonly associated with genes that are transcriptionally “poised”. The promoters of such genes harbor activating as well as repressive histone marks such that they are silenced, but they can be rapidly activated upon removal of the repressive marks. Our findings thus may explain how KSHV achieves efficient quiescence during latency, yet retains the potential to quickly revert to a fully active state upon induction of the lytic cycle.

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      Most cited references 67

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      A bivalent chromatin structure marks key developmental genes in embryonic stem cells.

      The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed "bivalent domains," consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.
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        Genome-wide maps of chromatin state in pluripotent and lineage-committed cells.

        We report the application of single-molecule-based sequencing technology for high-throughput profiling of histone modifications in mammalian cells. By obtaining over four billion bases of sequence from chromatin immunoprecipitated DNA, we generated genome-wide chromatin-state maps of mouse embryonic stem cells, neural progenitor cells and embryonic fibroblasts. We find that lysine 4 and lysine 27 trimethylation effectively discriminates genes that are expressed, poised for expression, or stably repressed, and therefore reflect cell state and lineage potential. Lysine 36 trimethylation marks primary coding and non-coding transcripts, facilitating gene annotation. Trimethylation of lysine 9 and lysine 20 is detected at satellite, telomeric and active long-terminal repeats, and can spread into proximal unique sequences. Lysine 4 and lysine 9 trimethylation marks imprinting control regions. Finally, we show that chromatin state can be read in an allele-specific manner by using single nucleotide polymorphisms. This study provides a framework for the application of comprehensive chromatin profiling towards characterization of diverse mammalian cell populations.
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          Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome.

          To gain insight into the function of DNA methylation at cis-regulatory regions and its impact on gene expression, we measured methylation, RNA polymerase occupancy and histone modifications at 16,000 promoters in primary human somatic and germline cells. We find CpG-poor promoters hypermethylated in somatic cells, which does not preclude their activity. This methylation is present in male gametes and results in evolutionary loss of CpG dinucleotides, as measured by divergence between humans and primates. In contrast, strong CpG island promoters are mostly unmethylated, even when inactive. Weak CpG island promoters are distinct, as they are preferential targets for de novo methylation in somatic cells. Notably, most germline-specific genes are methylated in somatic cells, suggesting additional functional selection. These results show that promoter sequence and gene function are major predictors of promoter methylation states. Moreover, we observe that inactive unmethylated CpG island promoters show elevated levels of dimethylation of Lys4 of histone H3, suggesting that this chromatin mark may protect DNA from methylation.
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            Author and article information

            Affiliations
            Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg, Germany
            Sanger Institute, United Kingdom
            Author notes

            Conceived and designed the experiments: TG AG. Performed the experiments: TG. Analyzed the data: TG AG. Wrote the paper: AG.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, USA )
            1553-7366
            1553-7374
            June 2010
            June 2010
            3 June 2010
            : 6
            : 6
            2880564
            20532208
            10-PLPA-RA-2419R2
            10.1371/journal.ppat.1000935
            (Editor)
            Günther, Grundhoff. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 19
            Categories
            Research Article
            Genetics and Genomics/Epigenetics
            Genetics and Genomics/Gene Expression
            Virology/Persistence and Latency
            Virology/Viral Replication and Gene Regulation
            Virology/Viruses and Cancer

            Infectious disease & Microbiology

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