Institute of Traditional Chinese Surgery, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China; Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA.
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA.
Toxicol Lett. 2020 Mar 15;321:131-137. doi: 10.1016/j.toxlet.2019.12.029. Epub 2019 Dec 23.
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".
先前暴露于化学物质/试剂可能以某种方式改变表观基因组，使得随后暴露于相同或不同的异源生物体会产生不同的反应。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，我们报道了二甲基亚砜（DMSO）对孕烷 X 受体（PXR）介导的基因调控的显著启动效应，并分析了其潜在的表观遗传机制。我们表明，DMSO（1.25-2.5%）预处理对增强 PXR 靶基因的表达有深远影响。这种启动效应持续长达 48 小时。在机制上，DMSO 预处理降低了 H4K12 乙酰化水平，从而增强了随后利福平刺激 PXR 靶基因 CYP3A4 调控区组蛋白 H4R3 甲基化。我们表明，蛋白质精氨酸甲基转移酶 1（PRMT1），它甲基化 H4R3，对于 DMSO 的启动作用很重要。通过药理学抑制剂腺苷二醛（AdoX）抑制甲基转移酶，或 PRMT1 的 RNAi 敲低，消除了 DMSO 的启动效应。另一方面，曲古抑菌素 A（TSA）预处理增加了组蛋白乙酰化水平，从而抑制了 H4R3 甲基化，也消除了 DMSO 的启动效应。基于以上观察，我们提出了一个在转录“接力”中组蛋白甲基化和乙酰化的顺序模型。
