title: Age-Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver.
abstract: 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). In all, 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., hsa-miR-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 >1,000 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.
authors.affiliation: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.|Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Burgess
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: S
authors.initials: S
authors.lastname: Philips
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Benson
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Desta
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: A
authors.initials: A
authors.lastname: Gaedigk
authors.affiliation: Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gaedigk
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Segar
authors.affiliation: Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana, USA.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: T C
authors.initials: TC
authors.lastname: Skaar
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D019295:Computational Biology; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007223:Infant; D008099:Liver / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010597:Pharmacogenetics
chemical_list: D035683:MicroRNAs