Klinge Carolyn M, Piell Kellianne M, Petri Belinda J, He Liqing, Zhang Xiang, Pan Jianmin, Rai Shesh N, Andreeva Kalina, Rouchka Eric C, Wahlang Banrida, Beier Juliane I, Cave Matthew C
Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY 40292, USA.
Department of Chemistry, University of Louisville College of Arts and Sciences, Louisville, KY 40292, USA.
Environ Epigenet. 2021 Sep 17;7(1):dvab008. doi: 10.1093/eep/dvab008. eCollection 2021.
Exposure to a single dose of polychlorinated biphenyls (PCBs) and a 12-week high-fat diet (HFD) results in nonalcoholic steatohepatitis (NASH) in mice by altering intracellular signaling and inhibiting epidermal growth factor receptor signaling. Post-transcriptional chemical modification (PTM) of RNA regulates biological processes, but the contribution of epitranscriptomics to PCB-induced steatosis remains unknown. This study tested the hypothesis that PCB and HFD exposure alters the global RNA epitranscriptome in male mouse liver. C57BL/6J male mice were fed a HFD for 12 weeks and exposed to a single dose of Aroclor 1260 (20 mg/kg), PCB 126 (20 µg/kg), both Aroclor 1260 and PCB 126 or vehicle control after 2 weeks on HFD. Chemical RNA modifications were identified at the nucleoside level by liquid chromatography-mass spectrometry. From 22 PTM global RNA modifications, we identified 10 significant changes in RNA modifications in liver with HFD and PCB 126 exposure. Only two modifications were significantly different from HFD control liver in all three PCB exposure groups: 2'-O-methyladenosine (Am) and N(6)-methyladenosine (m6A). Exposure to HFD + PCB 126 + Aroclor 1260 increased the abundance of N(6), O(2)-dimethyladenosine (m6Am), which is associated with the largest number of transcript changes. Increased m6Am and pseudouridine were associated with increased protein expression of the writers of these modifications: Phosphorylated CTD Interacting Factor 1 (PCIF1) and Pseudouridine Synthase 10 (PUS10), respectively, in HFD + PCB 126- + Aroclor 1260-exposed mouse liver. Increased N1-methyladenosine (m1A) and m6A were associated with increased transcript levels of the readers of these modifications: YTH N6-Methyladenosine RNA Binding Protein 2 (YTHDF2), YTH Domain Containing 2 (YTHDC2), and reader FMRP Translational Regulator 1 (FMR1) transcript and protein abundance. The results demonstrate that PCB exposure alters the global epitranscriptome in a mouse model of NASH; however, the mechanism for these changes requires further investigation.
单次暴露于多氯联苯（PCBs）以及12周的高脂饮食（HFD）会通过改变细胞内信号传导和抑制表皮生长因子受体信号传导，导致小鼠发生非酒精性脂肪性肝炎（NASH）。RNA的转录后化学修饰（PTM）可调节生物过程，但表观转录组学对多氯联苯诱导的脂肪变性的作用尚不清楚。本研究检验了以下假设：多氯联苯和高脂饮食暴露会改变雄性小鼠肝脏中的整体RNA表观转录组。C57BL/6J雄性小鼠接受12周的高脂饮食，并在高脂饮食2周后单次暴露于Aroclor 1260（20mg/kg）、多氯联苯126（20μg/kg）、Aroclor 1260和多氯联苯126或溶剂对照。通过液相色谱-质谱法在核苷水平鉴定化学RNA修饰。在22种整体RNA修饰中，我们鉴定出在高脂饮食和多氯联苯126暴露的肝脏中RNA修饰有10处显著变化。在所有三个多氯联苯暴露组中，只有两种修饰与高脂饮食对照肝脏有显著差异：2'-O-甲基腺苷（Am）和N（6）-甲基腺苷（m6A）。暴露于高脂饮食+多氯联苯126+Aroclor 1260会增加N（6），O（2）-二甲基腺苷（m6Am）的丰度，这与最大数量的转录本变化相关。在高脂饮食+多氯联苯126+Aroclor 1260暴露的小鼠肝脏中，m6Am和假尿苷增加分别与这些修饰的写入蛋白的表达增加有关：磷酸化CTD相互作用因子1（PCIF1）和假尿苷合酶10（PUS10）。N1-甲基腺苷（m1A）和m6A增加分别与这些修饰的读取蛋白的转录水平增加有关：YTH N6-甲基腺苷RNA结合蛋白2（YTHDF2）、含YTH结构域2（YTHDC2）以及读取蛋白FMRP翻译调节因子1（FMR1）的转录本和蛋白丰度。结果表明，多氯联苯暴露会改变非酒精性脂肪性肝炎小鼠模型中的整体表观转录组；然而，这些变化的机制需要进一步研究。
