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首页> 外文期刊>Molecular and Cellular Biology >ARTD1 Suppresses Interleukin 6 Expression by Repressing MLL1-Dependent Histone H3 Trimethylation
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ARTD1 Suppresses Interleukin 6 Expression by Repressing MLL1-Dependent Histone H3 Trimethylation

机译：ARTD1通过抑制MLL1依赖性组蛋白H3三甲基化抑制白介素6的表达。

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ADP-ribosyltransferase diphtheria-toxin like 1/poly(ADP-ribose) polymerase 1 (ARTD1/PARP1) is a chromatin-associated protein in the nucleus and plays an important role in different cellular processes such as regulation of gene transcription. ARTD1 has been shown to coregulate the inflammatory response by modulating the activity of the transcription factor nuclear factor κB (NF-κB), the principal regulator of interleukin 6 (IL-6), an important inflammatory cytokine implicated in a variety of diseases such as cancer. However, to what extent and how ARTD1 regulates IL-6 transcription has not been clear. Here, we show that ARTD1 suppresses lipopolysaccharide (LPS)-induced IL-6 expression in macrophages, without affecting the recruitment of the NF-κB subunit RelA to the IL-6 promoter and independent of its enzymatic activity. Interestingly, knockdown of ARTD1 did not alter H3 occupancy but increased LPS-induced trimethylation of histone 3 at lysine 4 (H3K4me3), a hallmark of transcriptionally active genes. We found that ARTD1 mediates its effect through the methyltransferase MLL1, by catalyzing H3K4me3 at the IL-6 promoter and forming a complex with NF-κB. These results demonstrate that ARTD1 modulates IL-6 expression by regulating the function of an NF-κB enhanceosome complex, which involves MLL1 and does not require ADP-ribosylation.
机译：像1 /聚（ADP-核糖）聚合酶1（ARTD1 / PARP1）一样，ADP-核糖基转移酶白喉毒素是细胞核中与染色质相关的蛋白质，并且在不同的细胞过程（例如调节基因转录）中起重要作用。已显示ARTD1可通过调节转录因子核因子κB（NF-κB）的活性来调节炎症反应，NF-κB是白介素6（IL-6）的主要调节因子，白介素6是一种重要的炎症细胞因子，与多种疾病有关，例如癌症。但是，尚不清楚ARTD1在何种程度上以及如何调控 IL-6 转录。在这里，我们显示ARTD1抑制巨噬细胞中脂多糖（LPS）诱导的 IL-6 表达，而不影响NF-κB亚基RelA向 IL-6 的募集。启动子和其酶活性无关。有趣的是，敲除ARTD1不会改变H3的占有率，但会增加LPS诱导的赖氨酸4（H3K4me3）组蛋白3的三甲基化，这是转录活性基因的标志。我们发现ARTD1通过在 IL-6 启动子处催化H3K4me3并与NF-κB形成复合物，通过甲基转移酶MLL1介导其作用。这些结果表明，ARTD1通过调节NF-κB增强体复合物的功能来调节 IL-6 表达，所述复合物涉及MLL1，不需要ADP-核糖基化。

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