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J. Biol. Chem., Vol. 282, Issue 45, 33210-33217, November 9, 2007

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Heat Shock Transcription Factor 1 Opens Chromatin Structure of Interleukin-6 Promoter to Facilitate Binding of an Activator or a Repressor^*

Sachiye Inouye, Mitsuaki Fujimoto, Tamami Nakamura, Eiichi Takaki, Naoki Hayashida, Tsonwin Hai, and Akira Nakai¹

From the Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Minami-Kogushi 1-1-1, Ube 755-8505, Japan and the Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210

Heat shock transcription factor 1 (HSF1) not only regulates expression of heat shock genes in response to elevated temperature, but is also involved in developmental processes by regulating genes such as cytokine genes. However, we did not know how HSF1 regulates non-heat shock genes. Here, we show that constitutive HSF1 binding to the interleukin (IL)-6 promoter is necessary for its maximal induction by lipopolysaccharide (LPS) stimulation in mouse embryo fibroblasts and peritoneal macrophages. Lack of HSF1 inhibited LPS-induced in vivo binding of an activator NF-B and a repressor ATF3 to IL-6 promoter. Neither NF-B nor ATF3 binds to the IL-6 promoter in unstimulated HSF1-null cells even if they were overexpressed. Treatment with histone deacetylase inhibitor or a DNA methylation inhibitor restored LPS-induced IL-6 expression in HSF1-null cells, and histone modification enzymes were recruited on the IL-6 promoter in the presence of HSF1. Consistently, chromatin structure of the IL-6 promoter in the presence of HSF1 was more open than that in its absence. These results indicate that HSF1 partially opens the chromatin structure of the IL-6 promoter for an activator or a repressor to bind to it, and provides a novel mechanism of gene regulation by HSF1.

Received for publication, May 31, 2007 , and in revised form, August 9, 2007.

^* This work was supported in part by grants-in-aid for Scientific Research and on Priority Areas, A Nuclear System of DECODE and Life of Proteins, from the Ministry of Education, Culture, Sports, Science and Technology, Japan, Uehara Foundation, NOVARTIS Foundation, Nakatomi Foundation, and the Kao Foundation for Arts and Sciences. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed. Tel.: 81-836-22-2214; Fax: 81-836-22-2315; E-mail: anakai{at}yamaguchi-u.ac.jp.

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