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Journal of Virology, November 2008, p. 10922-10931, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00865-08
Copyright © 2008, American Society for Microbiology. 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{triangledown}

Xue-feng Liu,1 Shixian Yan,1 Michael Abecassis,1,2*,{dagger} and Mary Hummel1,2,3,{dagger}

Transplant Division, Department of Surgery,1 Department of Microbiology and Immunology,2 Robert H. Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois3

Received 23 April 2008/ Accepted 19 August 2008

Human cytomegalovirus (CMV) is a ubiquitous herpesvirus with the ability to establish a lifelong latent infection. The mechanism by which this occurs is not well understood. Regulation of, for example, immediate-early (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 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 major IE promoter (MIEP) in the kidneys of acutely and latently infected mice. Our studies show that, like herpes simplex virus, murine CMV 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 heterochromatin protein 1{gamma} and Yin-Yang 1 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.

* Corresponding author. Mailing address: Division of Organ Transplantation, Northwestern Memorial Hospital, 675 N. St. Clair St., Galter Pavilion, Suite 17-200, Chicago, IL 60611. Phone: (312) 695-0359. Fax: (312) 695-1817. E-mail: mabecass{at}nmh.org

{triangledown} Published ahead of print on 27 August 2008.

{dagger} Michael Abecassis and Mary Hummel were co-senior authors of this report.

Journal of Virology, November 2008, p. 10922-10931, Vol. 82, No. 21
0022-538X/08/$08.00+0     doi:10.1128/JVI.00865-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yuan, J., Liu, X., Wu, A. W., McGonagill, P. W., Keller, M. J., Galle, C. S., Meier, J. L. (2009). Breaking Human Cytomegalovirus Major Immediate-Early Gene Silence by Vasoactive Intestinal Peptide Stimulation of the Protein Kinase A-CREB-TORC2 Signaling Cascade in Human Pluripotent Embryonal NTera2 Cells. J. Virol. 83: 6391-6403 [Abstract] [Full Text]  


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