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.
|Original language||English (US)|
|Number of pages||8|
|Journal||Biochemical and Biophysical Research Communications|
|State||Published - Mar 7 2014|
Bibliographical noteFunding Information:
We are deeply thankful to Dr. Jatinder K. Lamba for her insightful comments and suggestions on the paper. Research was supported by the Building Interdisciplinary Research Careers in Women’s Health Grant (# K12HD055887) from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (NICHD) , the Office of Research on Women’s Health, and the National Institute on Aging , NIH , administered by the University of Minnesota Deborah E. Powell Center for Women’s Health. The content is solely the responsibility of the authors and does not necessarily represent the office views of the NICHD or NIH.
- Cytochrome P450
- Transcriptional regulation
- mRNA expression