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J. Biol. Chem., Vol. 281, Issue 49, 37652-37660, December 8, 2006

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Human Daxx-mediated Repression of Human Cytomegalovirus Gene Expression Correlates with a Repressive Chromatin Structure around the Major Immediate Early Promoter^*

David L. Woodhall¹, Ian J. Groves, Matthew B. Reeves, Gavin Wilkinson, and John H. Sinclair²

From the Department of Medicine, University of Cambridge, Cambridge CB2 2QQ, United Kingdom and Section for Infection and Immunity, College of Medicine, University of Wales, Heath Park, Cardiff CF14 4XX, Wales, United Kingdom

Upon herpesvirus infection, viral DNA becomes associated with nuclear structures known as nuclear domain 10 (ND10). The role of ND10 during herpesvirus infection has long been contentious; data arguing for a role for ND10 in repression of infection have been countered by other data showing little effect of ND10 on virus infection. Here we show that knockdown of human Daxx (hDaxx) expression, an important component of ND10, prior to infection with human cytomegalovirus resulted in increased levels of viral immediate early RNA and protein expression and that this correlated with an increased association of the major immediate early promoter with markers of transcriptionally active chromatin. Conversely, we also show that stable overexpression of hDaxx renders cells refractory to cytomegalovirus immediate early gene expression. Intriguingly, this hDaxx-mediated repression appears to be restricted to cells stably overexpressing hDaxx and is not recapitulated in transient transfection assays. Finally, hDaxx-mediated repression of cytomegalovirus major immediate early gene expression was overcome by infecting at higher virus titers, suggesting that an incoming viral structural protein or viral DNA is responsible for overcoming the repression of viral gene expression in hDaxx superexpressing cells. These data suggest that hDaxx in ND10 functions at the site of cytomegalovirus genome deposition to repress transcription of incoming viral genomes and that this repression is mediated by a direct and immediate effect of hDaxx on chromatin modification around the viral major immediate early promoter.

Received for publication, May 4, 2006 , and in revised form, September 7, 2006.

^* This work was supported by grants from the United Kingdom Medical Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 01239.

² To whom correspondence should be addressed: Dept. of Medicine, Level 5 Box 157, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom. Tel.: 44-1223-336850; E-mail: js{at}mole.bio.cam.ac.uk.

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