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Journal of Virology, March 2003, p. 3394-3401, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3394-3401.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Glial Cell-Specific Regulation of the JC Virus Early Promoter by Histone Deacetylase Inhibitors

So-Young Kim,1 Moon-Sook Woo,2 Won-Ki Kim,3 Eung-Chil Choi,1* John W. Henson,4 and Hee-Sun Kim2*

Department of Neuroscience,2 Department of Pharmacology, Ewha Institute of Neuroscience, College of Medicine, Ewha Womans University,3 College of Pharmacy, Seoul National University, Seoul, South Korea,1 Molecular Neuro-Oncology Laboratory, Harvard Medical School, Charlestown, Massachusetts 021294

Received 20 September 2002/ Accepted 17 December 2002

The human polyomavirus JC virus is the etiologic agent of the fatal disease demyelinating progressive multifocal leukoencephalopathy. Although multiple transcription factors have been shown to interact with the JC virus promoter and regulate transcriptional activity, their relevance to cell specificity remains elusive. To investigate whether chromatin structure controls glial cell-specific expression of JC virus early genes, glial and nonglial cells were transfected with a reporter plasmid containing the JC virus early promoter and then treated with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate. TSA and butyrate induced 20- to 30-fold activation of the JC virus promoter in nonglial cells, whereas less than 2-fold induction was observed in glial cells. These results indicate that the JC virus early promoter might be highly suppressed in nonglial cells by hypoacetylated chromatin and activated by hyperacetylation. In support of this, chromatin immunoprecipitation assays demonstrated acetylation of the JC virus promoter region in U87MG cells but no acetylation in HeLa cells. In addition, treatment of HeLa cells with TSA induced hyperacetylation of the JC virus promoter, whereas minimal induction was seen in U87MG cells. Deletional and site-directed mutational analyses revealed that the enhancer region and Sp1 binding site upstream of the TATA box were important for TSA-mediated activation. We confirmed TSA-mediated activation of the JC virus promoter in the context of natural chromatin structure in stable cell lines. Thus, it appears that chromatin structure may control JC virus transcription in a cell-specific manner.

* Corresponding author. Mailing address for Eung-Chil Choi: College of Pharmacy, Seoul National University, San 56-1, Shillim-Dong, Kwanak-Gu, Seoul 151-742, South Korea. Phone: 82 2 880 7874. Fax: 82 2 886 5802. E-mail: ecchoi{at}snu.ac.kr.

* Corresponding author. Mailing address for Hee-Sun Kim: Ewha Institute of Neuroscience, Ewha University Medical School, 70 Jongno 6-Ga, Jongno-Gu, Seoul 110-783, South Korea. Phone: 82 2 760 5502. Fax: 82 2 760 5524. E-mail: hskimp{at}mm.ewha.ac.kr.

Journal of Virology, March 2003, p. 3394-3401, Vol. 77, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.6.3394-3401.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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