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J. Biol. Chem., Vol. 279, Issue 39, 40362-40367, September 24, 2004

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Histone Deacetylase Activity Is Required to Recruit RNA Polymerase II to the Promoters of Selected Interferon-stimulated Early Response Genes^*

Shuji Sakamoto, Ramesh Potla, and Andrew C. Larner

From the Department of Immunology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

Posttranslational modification of histones by acetylation, methylation or phosphorylation has emerged as a major mechanism to modify chromatin structure and gene expression. In most cases, transcriptionally active genes display enhanced binding of acetylated histones in their promoters. Activation of histone acetyltransferases or inhibition of histone deacetylases (HDACs) allows chromatin to assume a more open state permitting transcriptional activators to form a preinitiation complex. To our surprise, treatment of cells with the HDAC inhibitor, trichostatin A (TSA), inhibits selected interferon (IFN)-stimulated immediate early genes that are activated by the transcription factors Stat1 and Stat2. However, IFN activation of IRF-1, which requires tyrosine-phosphorylated Stat1 homodimers binding to a interferon activation sequence in its promoter is not affected by TSA. Exposure of cells to TSA does not alter tyrosine phosphorylation of Stat1 or Stat2. TSA treatment of cells also does not alter the binding of Stat 1 or Stat2 to the endogenous ISG54 promoter. However, IFN-stimulated binding of RNA polymerase II to the ISG54 promoter is prevented by TSA. Interestingly, ectopic expression of IRF9 reverses the inhibitory actions of TSA, suggesting that IRF9 functions to recruit RNA polymerase II to the promoter of interferon-stimulated genes. This particular function of IRF9 requires the activity of histone deacetylases.

Received for publication, June 8, 2004

^* This work was supported by National Institutes of Health Grant CA77366. 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.

To whom correspondence should be addressed. Tel.: 216-445-9045; Fax: 216-444-8372; E-mail: larnera{at}ccf.org.

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