The Long Noncoding RNA Hepatocyte Nuclear Factor 4α Antisense RNA 1 Negatively Regulates Cytochrome P450 Enzymes in Huh7 Cells via Histone Modifications
| العنوان: | The Long Noncoding RNA Hepatocyte Nuclear Factor 4α Antisense RNA 1 Negatively Regulates Cytochrome P450 Enzymes in Huh7 Cells via Histone Modifications |
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| المؤلفون: | Shengna Han, Lirong Zhang, Shitong Chen, Kun Yang, Liang Yan, Xiao-bo Zhong, Pei Wang, Xiaofei Wang, Yiting Wang |
| المصدر: | Drug Metabolism and Disposition. 49:361-368 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Pharmacology, endocrine system, Gene knockdown, Pregnane X receptor, biology, Chemistry, Pharmaceutical Science, Aryl hydrocarbon receptor, digestive system, 030226 pharmacology & pharmacy, Antisense RNA, Cell biology, 03 medical and health sciences, Hepatocyte nuclear factors, 0302 clinical medicine, Nuclear receptor, 030220 oncology & carcinogenesis, Gene expression, Constitutive androstane receptor, polycyclic compounds, biology.protein |
| الوصف: | The maintenance of homeostasis of cytochromes P450 enzymes (P450s) under both physiologic and xenobiotic exposure conditions is ensured by the action of positive and negative regulators. In the current study, the hepatocyte nuclear factor 4α (HNF4A) antisense RNA 1 (HNF4A-AS1), an antisense long noncoding RNA of HNF4A, was found to be a negative regulator of the basal and rifampicin (RIF)-induced expression of nuclear receptors and downstream P450s. In Huh7 cells, knockdown of HNF4A-AS1 resulted in elevated expression of HNF4A, pregnane X receptor (PXR), and P450s (including CYP3A4) under both basal and RIF-induced conditions. Conversely, overexpression of HNF4A-AS1 led to decreased basal expression of constitutive androstane receptor, aryl hydrocarbon receptor, PXR, and all studied P450s. Of note, significantly diminished induction levels of PXR and CYP1A2, 2C8, 2C19, and 3A4 by RIF were also observed in HNF4A-AS1 plasmid-transfected Huh7 cells. Moreover, the negative feedback of HNF4A on HNF4A-AS1-mediated gene expression was validated using a loss-of-function experiment in this study. Strikingly, our data showed that increased enrichment levels of histone 3 lysine 4 trimethylation and HNF4A in the CYP3A4 promoter contribute to the elevated CYP3A4 expression after HNF4A-AS1 knockdown. Overall, the current study reveals that histone modifications contribute to the negative regulation of nuclear receptors and P450s by HNF4A-AS1 in basal and drug-induced levels. SIGNIFICANCE STATEMENT: Utilizing loss-of-function and gain-of-function experiments, the current study systematically investigated the negative regulation of HNF4A-AS1 on the expression of nuclear receptors (including HNF4A, constitutive androstane receptor, aryl hydrocarbon receptor, and pregnane X receptor) and P450s (including CYP1A2, 2E1, 2B6, 2D6, 2C8, 2C9, 2C19, and 3A4) in both basal and rifampicin-induced levels in Huh7 cells. Notably, this study is the first to reveal the contribution of histone modification to the HNF4A-AS1-mediated expression of CYP3A4 in Huh7 cells. |
| تدمد: | 1521-009X 0090-9556 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::3cb0a1307fc4c1944db887647d5953dd https://doi.org/10.1124/dmd.120.000316 |
| رقم الأكسشن: | edsair.doi...........3cb0a1307fc4c1944db887647d5953dd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1521009X 00909556 |
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