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J. Virol. doi:10.1128/JVI.00865-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Establishment of Murine Cytomegalovirus Latency in vivo is Associated with Changes in Histone Modifications and Recruitment of Transcriptional Repressors to the Major Immediate Early Promoter

Transplant Division, Department of Surgery, Department of Microbiology and Immunology, Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL

^* To whom correspondence should be addressed. Email: mabecass{at}nmh.org.

	Abstract

Human cytomegalovirus (HCMV) is a ubiquitous herpesvirus with the ability to establish a lifelong latent infection. The mechanism by which this occurs has not been well understood. Regulation of ie gene expression is thought to be a critical control point in transcriptional control of the switch between latency and reactivation. Here, we present evidence that supports previous studies showing that the majority of genomes are quiescent with respect to ie gene expression. To study the possible role of epigenetic factors that may be involved in repression of ie gene expression in latency, we have analyzed changes in the patterns of modifications of histones bound to the MIEP in the kidneys of acutely and latently infected mice. Our studies show that, like HSV, MCMV genomes become relatively enriched in histones in latent infection. There are dramatic changes in modifications of histones associated with the MIEP when latency is established: H3 and H4 become hypoacetylated and H3 is hypomethylated at lysine 4, while H3 lysine 9 is hypermethylated in latently infected mice. These changes are accompanied by a relative loss of RNA polymerase and gain of HP-1 and YY1 bound to the MIEP. Our studies suggest that, in the majority of cells, CMV establishes a true latent infection, defined as the lack of expression of genes associated with productive infection, and that this occurs through changes in histone modifications and recruitment of transcriptional silencing factors to the MIEP.