Epigenetic sensitization of pregnane X receptor-regulated gene expression by dimethyl sulfoxide. (15th March 2020)

• Record Type: Journal Article
• Authors: Xie, Ying; Ke, Sui; Chen, Jingshu; Ouyang, Nengtai; Tian, Yanan
• Is Part Of: Toxicology letters. Volume 321(2020)
• Page Start: 131
• Page End: 137
• Publication Date: 2020-03-15
• Subjects: PXR pregnane X receptor -- PRMT1 protein arginine methyltransferase 1 -- DMSO dimethyl sulfoxide; Pregnane X -- Receptor -- Histone modification -- Gene regulation -- Priming effect; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2019.12.029
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: DMSO pretreatment can enhance PXR-regulated gene expression by ligand activation. PRMT1 is essential for this time and dose-dependent "priming" effect. The interplay between H4R3me and H4 acetylation is critical for this "priming". DMSO treatment can also cause G0/G1 arrest of HepG2 cells in spite of PXR expression. PRMT1 also interacts with RXR, which may indicate broader "priming" effects. Abstract: 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".