Prior exposures to chemicals/agents may alter epigenome in such a way that subsequent exposure to the same or different xenobiotic would produce different responses. Understanding the mechanism for this "priming" effect is of clinical significance in avoiding adverse drug-drug interactions. Here we reported a dramatic priming effect of dimethyl sulfoxide (DMSO) on pregnane X receptor (PXR)-mediated gene regulations and analyzed the underpinning epigenetic mechanism. We showed that DMSO (1.25-2.5%) pretreatment has a profound effect in enhancing the expression of PXR target genes. This priming effect persisted up to 48 h. Mechanistically, DMSO pretreatment reduced H4K12 acetylation and therefore enhanced the subsequent rifampicin stimulated histone H4R3 methylation on the regulatory region of PXR target gene CYP3A4. We showed that protein arginine methyltransferase 1 (PRMT1), which methylates H4R3, was important for priming by DMSO. Inhibition of methyltransferase by the pharmacological inhibitor adenosine dialehyde (AdoX), or RNAi knockdown of PRMT1, abolished the DMSO priming effects. On the other hand, Trichostation A (TSA) pretreatment, which increases histone acetylation and therefore suppresses H4R3 methylation, also abolished the DMSO priming effects. Based on the above observation, we proposed a model of sequential order of histone methylation and acetylation on the transcription "relay".

中文翻译：

---

二甲亚砜对孕烷 X 受体调节基因表达的表观遗传致敏

先前接触化学品/药剂可能会改变表观基因组，随后接触相同或不同的异生物质会产生不同的反应。了解这种“启动”效应的机制对于避免不良的药物相互作用具有临床意义。在这里，我们报告了二甲基亚砜 (DMSO) 对孕烷 X 受体 (PXR) 介导的基因调控的显着启动效应，并分析了基础的表观遗传机制。我们表明 DMSO (1.25-2.5%) 预处理对增强 PXR 靶基因的表达具有深远的影响。这种启动效应持续长达 48 小时。从机制上讲，DMSO 预处理减少了 H4K12 乙酰化，因此增强了随后利福平刺激的 PXR 靶基因 CYP3A4 调控区的组蛋白 H4R3 甲基化。我们表明，甲基化 H4R3 的蛋白质精氨酸甲基转移酶 1 (PRMT1) 对 DMSO 引发很重要。药理抑制剂腺苷二醛 (AdoX) 或 RNAi 敲低 PRMT1 对甲基转移酶的抑制作用消除了 DMSO 引发效应。另一方面，Trichostation A (TSA) 预处理会增加组蛋白乙酰化并因此抑制 H4R3 甲基化，也消除了 DMSO 引发效应。基于上述观察，我们提出了转录“中继”上组蛋白甲基化和乙酰化顺序的模型。另一方面，Trichostation A (TSA) 预处理会增加组蛋白乙酰化并因此抑制 H4R3 甲基化，也消除了 DMSO 引发效应。基于上述观察，我们提出了转录“中继”上组蛋白甲基化和乙酰化顺序的模型。另一方面，Trichostation A (TSA) 预处理会增加组蛋白乙酰化并因此抑制 H4R3 甲基化，也消除了 DMSO 引发效应。基于上述观察，我们提出了转录“中继”上组蛋白甲基化和乙酰化顺序的模型。