Molecular mechanism of transcriptional regulation of IL-6 gene by heat shock transcription factor

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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 molecular mechanisms how HSF1 regulates non-heat shock genes. Here, we showed that constitutive HSF1 binding to IL-6 promoter is necessary for its maximal induction by LPS-stimulation in mouse embryo fibroblasts and peritoneal macrophages. Lack of HSF1 inhibited LPS-induced in vivo binding of an activator NF-kB and a repressor ATF3 to IL-6 promoter. Neither NF-kB nor ATF3 binds to 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 IL-6 promoter in the presence of HSF1. Consistently, chromatin structure of IL-6 promoter in the presence of HSF1 was more opened than that in its absence. These results indicate that HSF1 partially opens chromatin structure of IL-6 promoter for an activator or a repressor to bind to it, and provides a novel mechanism of gene regulation by HSF1