The histone deacetylases (HDACs) are a superfamily of chromatin-modifying enzymes that silence transcription through the modification of histones. Among them, HDAC3 is unique in that interaction with nuclear receptor corepressors 1 and 2 (NCoR1/2) is required to engage its catalytic activity1–3. However, global loss of HDAC3 also results in the repression of transcription, the mechanism of which is currently unclear4–8. Here we report that, during the activation of macrophages by lipopolysaccharides, HDAC3 is recruited to activating transcription factor 2 (ATF2)-bound sites without NCoR1/2 and activates the expression of inflammatory genes through a non-canonical mechanism. By contrast, the deacetylase activity of HDAC3 is selectively engaged at ATF3-bound sites that suppress Toll-like receptor signalling. Loss of HDAC3 in macrophages safeguards mice from lethal exposure to lipopolysaccharides, but this protection is not conferred upon genetic or pharmacological abolition of the catalytic activity of HDAC3. Our findings show that HDAC3 is a dichotomous transcriptional activator and repressor, with a non-canonical deacetylase-independent function that is vital for the innate immune system. During the activation of mouse macrophages by lipopolysaccharides, histone deacetylase 3 controls inflammatory responses by both repressing and activating gene transcription depending on its differential association with transcription factors.

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HDAC3活性的二分参与控制炎症反应

组蛋白去乙酰化酶 (HDAC) 是染色质修饰酶的超家族，通过组蛋白的修饰使转录沉默。其中，HDAC3 的独特之处在于需要与核受体辅阻遏物 1 和 2 (NCoR1/2) 相互作用才能发挥其催化活性 1-3。然而，HDAC3 的整体缺失也会导致转录抑制，其机制目前尚不清楚 4-8。在这里，我们报告说，在脂多糖激活巨噬细胞的过程中，HDAC3 被招募到激活转录因子 2 (ATF2) 结合位点而没有 NCoR1/2 并通过非典型机制激活炎症基因的表达。相比之下，HDAC3 的脱乙酰酶活性选择性地参与抑制 Toll 样受体信号传导的 ATF3 结合位点。巨噬细胞中 HDAC3 的缺失可保护小鼠免于致命地暴露于脂多糖，但这种保护并未赋予 HDAC3 催化活性的遗传或药理学消除。我们的研究结果表明，HDAC3 是一种二分转录激活因子和抑制因子，具有对先天免疫系统至关重要的非典型脱乙酰酶独立功能。在脂多糖激活小鼠巨噬细胞期间，组蛋白去乙酰化酶 3 通过抑制和激活基因转录来控制炎症反应，这取决于其与转录因子的差异关联。我们的研究结果表明，HDAC3 是一种二分转录激活因子和抑制因子，具有对先天免疫系统至关重要的非典型脱乙酰酶独立功能。在脂多糖激活小鼠巨噬细胞期间，组蛋白去乙酰化酶 3 通过抑制和激活基因转录来控制炎症反应，这取决于其与转录因子的差异关联。我们的研究结果表明，HDAC3 是一种二分转录激活因子和抑制因子，具有对先天免疫系统至关重要的非典型脱乙酰酶独立功能。在脂多糖激活小鼠巨噬细胞期间，组蛋白去乙酰化酶 3 通过抑制和激活基因转录来控制炎症反应，这取决于其与转录因子的差异关联。