Age-Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver.
Age-Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver.
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DOI：
10.1002/cpt.145
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发表时间：
2015-08
影响因子：
6.7
通讯作者：
Skaar TC
中科院分区：
文献类型：
--
作者：
Burgess KS;Philips S;Benson EA;Desta Z;Gaedigk A;Gaedigk R;Segar MW;Liu Y;Skaar TC
肝脏的发育变化会显着影响药物的分布。由于 microRNA (miRNA) 作为药物处置基因表达的重要调节因子的出现，我们研究了 miRNA 表达的年龄依赖性变化。在 90 个人类肝脏组织（胎儿、儿童（1-17 岁）和成人（28-80 岁）；每个 n=30）中测量了 533 个 miRNA 的表达。从胎儿到儿童，有 114 个 miRNA 上调，72 个 miRNA 下调；从儿童到成人，分别有 2 个和 3 个 miRNA 下调。在发育变化的 miRNA 中，预测或实验验证了 99 个 miRNA-mRNA 相互作用（例如 hsamiR-125b-5p-CYP1A1；hsa-miR-34a-5p-HNF4A）。在人类肝脏样本（每个 n=10）中，通过 RNA 测序分析，观察到超过 1000 个 miRNA 的表达与药物处置和调节基因的 mRNA 之间存在显着的负相关。我们的数据揭示了胎儿和儿童发育期之间肝脏基因表达显着变化的机制，并支持这些年龄依赖性 miRNA 在调节药物处置中的作用。
Developmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric (1-17 years), and adult (28-80 years); n=30 each). 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g. hsamiR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n=10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition.