title: microRNA-34a is associated with expression of key hepatic transcription factors and cytochromes P450.
abstract: microRNA (miRNA) mediated regulation of gene expression has emerged as a significant mechanism contributing to variation in gene expression. In this study, we evaluated the potential role of miRNAs in regulating expression of hepatic cytochromes P450 and their transcriptional regulatory genes. We screened the Targetscan database for high scoring miRNA binding site predictions in selected hepatic DMEs and transcription factors. Expression profiling for candidate miRNAs (n=22) and their target genes (n=20) was performed in 50 human liver samples (25 female, 25 male). Significant negative correlations were observed between expression levels of several CYPs/hepatic transcription factors and the hepatic miRNAs studied. Interestingly, hepatic miR-34a demonstrated significant negative correlation with expression levels of multiple hepatic transcription factors (including NR1I2 and HNF4α) and DMEs (CYP3A4, CYP2C19). miR-34a expression was also significantly higher in males than in females in congruence with previous observations of higher CYP3A4 expression in females versus males. A mediation analysis revealed that miR-34a was involved in significant mediation of the association observed between CYP2C19 and several hepatic transcription factors (HNF4α, NR1I2). miR-34a may thus play a key regulatory role and be a key contributory factor to the inter-individual variability observed in expression of key drug metabolizing genes in humans.
authors: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, United States. Electronic address: lamba005@umn.edu.
authors: V
authors: V
authors: Lamba
authors: Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, United States.
authors: Y
authors: Y
authors: Ghodke
authors: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States.
authors: W
authors: W
authors: Guan
authors: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States.
authors: T S
authors: TS
authors: Tracy
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D012737:Sex Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System
keywords: Cytochrome P450; Gender; Hepatic; Transcriptional regulation; mRNA expression; microRNA