Glial cell-specific regulation of the JC virus early promoter by histone deacetylase inhibitors.
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.
Kim
So-Young
SY
Ewha Institute of Neuroscience, College of Medicine, Ewha Womans University, Seoul, South Korea.
Woo
Moon-Sook
MS
Kim
Won-Ki
WK
Choi
Eung-Chil
EC
Henson
John W
JW
Kim
Hee-Sun
HS
D000107:Acetylation; D002087:Butyrates / Q000494:pharmacology; D002843:Chromatin / Q000502:physiology; D004742:Enhancer Elements, Genetic; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007577:JC Virus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D009457:Neuroglia / Q000821:virology*; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D002087:Butyrates; D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016329:Sp1 Transcription Factor; D014764:Viral Proteins; C012589:trichostatin A