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,Akira Nakai

doi:10.1074/jbc.m704471200

Sachiye Inouye, Mitsuaki Fujimoto + Show 5 more

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https://doi.org/10.1074/jbc.m704471200

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Abstract

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-kappaB and a repressor ATF3 to IL-6 promoter. Neither NF-kappaB 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.

Highlights

Shock elements (HSE) [3]
mouse embryo fibroblast (MEF) cells plated in 100-mm dishes containing 10 ml of Heat shock transcription factor 1 (HSF1) Is Required for Maximal Induction of IL-6 Expression—
Medium were infected with Ad-HSF1 and Adenoviruses We showed previously that HSF1 is required for IL-6 to be expressing HSF1 mutants at a titer of 8 ϫ 105 pfu/ml, Ad- maximally induced in cultured spleen cells and peritoneal macrophages in response to LPS treatment [14]

Summary

Introduction

Shock elements (HSE) [3]. In addition to protecting cells from exposure to extreme temperature by inducing Hsp [4, 5], HSFs play critical functions in developmental processes such as gamategenesis and neurogenesis (6 –9), in maintenance of the sensory organs (10 –13), and in immune response [14, 15], partly by regulating expression of development-related genes such as FGF, LIF, and IL-6 cytokine genes and the p35 gene, an activator of cyclin-dependent kinase 5 as well as Hsp genes [9, 11, 13, 14]. HSF1 inhibits expression of tumor necrosis factor-␣ and IL-1␤ by binding directly to the tumor necrosis factor-␣ promoter [16], or by physically interacting with NFIL6, an activator for the IL-1␤ gene [17]. It is still unclear how HSF1 regulates expression of non-heat shock genes. We found a novel function of HSF1 that partially opens the chromatin structure of the IL-6 promoter for an activator or a repressor to bind to it in unstressed conditions

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