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

热休克转录因子1（HSF 1）不仅调节热休克基因在高温下的表达，而且还通过调节细胞因子等基因参与发育过程。然而，我们不知道HSF 1如何调节非热休克基因的分子机制。在这里，我们表明，组成型HSF 1结合IL-6启动子是必要的，其最大的诱导LPS刺激小鼠胚胎成纤维细胞和腹腔巨噬细胞。缺乏HSF 1抑制LPS诱导的激活因子NF-κ B和阻遏因子ATF 3与IL-6启动子的体内结合。在未受刺激的HSF 1-null细胞中，NF-kB和ATF 3都不与IL-6启动子结合，即使它们过表达。用组蛋白去乙酰化酶抑制剂或DNA甲基化抑制剂处理恢复了HSF 1缺失细胞中LPS诱导的IL-6表达，并且在HSF 1存在下，组蛋白修饰酶在IL-6启动子上被募集。与此同时，IL-6启动子的染色质结构在HSF 1存在时比在HSF 1不存在时更加开放。这些结果表明，HSF 1部分打开了IL-6启动子的染色质结构，使激活子或阻遏子与其结合，并提供了HSF 1基因调控的新机制

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