microRNA-34a is associated with expression of key hepatic transcription factors and cytochromes P450.
microRNA-34a is associated with expression of key hepatic transcription factors and cytochromes P450.
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DOI：
10.1016/j.bbrc.2014.02.024
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发表时间：
2014-03-07
影响因子：
3.1
通讯作者：
Tracy, T. S.
中科院分区：
文献类型：
--
作者：
Lamba, V.;Ghodke, Y.;Guan, W.;Tracy, T. S.
microRNA （miRNA）介导的基因表达调控已成为导致基因表达变异的重要机制。在这项研究中，我们评估了mirna在调节肝细胞色素p450及其转录调控基因表达中的潜在作用。我们筛选Targetscan数据库，在选定的肝脏DMEs和转录因子中获得高分miRNA结合位点预测。在50份人类肝脏样本（25名女性，25名男性）中对候选mirna （n= 22）及其靶基因（n=21）进行表达谱分析。几种CYPs/肝脏转录因子的表达水平与所研究的肝脏mirna呈显著负相关。有趣的是，肝脏miR-34a与多种肝脏转录因子（包括NR1I2和HNF4α）和DMEs （CYP3A4, CYP2C19）的表达水平呈显著负相关。miR-34a在男性中的表达也显著高于女性，这与之前观察到的CYP3A4在女性中的表达高于男性一致。中介分析显示，miR-34a参与了CYP2C19与几种肝脏转录因子（HNF4α, NR1I2）之间关联的显著中介。因此，miR-34a可能起着关键的调节作用，是人类关键药物代谢基因表达的个体间差异的关键促成因素。
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 cytochrome P450s 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=21) 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.
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影响因子：
13.5
作者：
Braconi, Chiara;Huang, Nianyuan;Patel, Tushar
通讯作者：
Patel, Tushar
影响因子：
7.6
作者：
BARON, RM;KENNY, DA
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
5
作者：
Liffers, Sven-T;Munding, Johanna B.;Tannapfel, Andrea
通讯作者：
Tannapfel, Andrea
影响因子：
5
作者：
Magrelli, Armando;Azzalin, Gianluca;Taruscio, Domenica
通讯作者：
Taruscio, Domenica