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Journal of Virology, June 2006, p. 5740-5746, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.00169-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Trimethylation of Histone H3 Lysine 4 by Set1 in the Lytic Infection of Human Herpes Simplex Virus 1

Jing Huang,^1, Jennifer R. Kent,^2, Brandon Placek,¹ Kelly A. Whelan,¹ Charles M. Hollow,² Ping-Yao Zeng,¹ Nigel W. Fraser,² and Shelley L. Berger^1*

Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, Pennsylvania,¹ Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania²

Received 25 January 2006/ Accepted 22 March 2006

Human herpes simplex virus 1 (HSV-1) is a double-stranded DNA virus that causes facial, ocular, and encephalitic disease in humans. Previous work showed that the genome of HSV-1 is associated with acetylated and methylated histones during lytic infection. However, the physiological role of histone modifications in lytic infection of HSV-1 is unclear. We examined the role of protein methylation in lytic infection of HSV-1 using a protein methylation inhibitor, 5'-deoxy-5'-methylthioadenosine (MTA). We found that MTA strongly reduces the transcription and replication of HSV-1. Moreover, MTA treatment decreases the level of trimethylation of lysine 4 in histone H3 (H3K4me3) on the HSV-1 genome. These results suggest that protein methylation, and in particular, histone methylation, is involved in the lytic infection of HSV-1. To delineate the underlying mechanism, we investigated the role of two H3K4 methyltransferases, Set1 and Set7/9, in the lytic infection of HSV-1. Using small interference RNA, we found that the reduction of Set1, but not Set7/9, reduces the transcription and replication of HSV-1 and specifically decreases H3K4me3 on the virus genome. These results indicate that H3K4me3 mediated by Set1 is required for optimal gene expression and replication of HSV-1 during lytic infection and suggest that this pathway could be a potential point of pharmacological intervention during HSV-1 infection.

J.H. and J.R.K. contributed equally to this study.

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