title: Bioinformatic analysis of microRNA networks following the activation of the constitutive androstane receptor (CAR) in mouse liver.
abstract: The constitutive androstane receptor (CAR; NR1I3) is a member of the nuclear receptor superfamily that functions as a xenosensor, serving to regulate xenobiotic detoxification, lipid homeostasis and energy metabolism. CAR activation is also a key contributor to the development of chemical hepatocarcinogenesis in mice. The underlying pathways affected by CAR in these processes are complex and not fully elucidated. MicroRNAs (miRNAs) have emerged as critical modulators of gene expression and appear to impact many cellular pathways, including those involved in chemical detoxification and liver tumor development. In this study, we used deep sequencing approaches with an Illumina HiSeq platform to differentially profile microRNA expression patterns in livers from wild type C57BL/6J mice following CAR activation with the mouse CAR-specific ligand activator, 1,4-bis-[2-(3,5,-dichloropyridyloxy)] benzene (TCPOBOP). Bioinformatic analyses and pathway evaluations were performed leading to the identification of 51 miRNAs whose expression levels were significantly altered by TCPOBOP treatment, including mmu-miR-802-5p and miR-485-3p. Ingenuity Pathway Analysis of the differentially expressed microRNAs revealed altered effector pathways, including those involved in liver cell growth and proliferation. A functional network among CAR targeted genes and the affected microRNAs was constructed to illustrate how CAR modulation of microRNA expression may potentially mediate its biological role in mouse hepatocyte proliferation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
authors.affiliation: DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, Delaware, United States; Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States.
authors.forename: Ruixin
authors.initials: R
authors.lastname: Hao
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States.
authors.forename: Shengzhong
authors.initials: S
authors.lastname: Su
authors.affiliation: Department of Bioinformatics and Genomics, The Pennsylvania State University, University Park, PA, United States.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Statistics, The Pennsylvania State University, University Park, PA, United States.
authors.forename: Frank
authors.initials: F
authors.lastname: Shen
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States.
authors.forename: Ben
authors.initials: B
authors.lastname: Niu
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States.
authors.forename: Denise M
authors.initials: DM
authors.lastname: Coslo
authors.affiliation: Department of Bioinformatics and Genomics, The Pennsylvania State University, University Park, PA, United States.
authors.forename: Istvan
authors.initials: I
authors.lastname: Albert
authors.affiliation: DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, Delaware, United States.
authors.forename: Xing
authors.initials: X
authors.lastname: Han
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, United States. Electronic address: cjo10@psu.edu.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Omiecinski
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology; D000090702:Constitutive Androstane Receptor; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015723:Gene Library; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D007274:Injections, Intraperitoneal; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D058977:Molecular Sequence Annotation; D061251:Primary Cell Culture; D011725:Pyridines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000090702:Constitutive Androstane Receptor; D008024:Ligands; D035683:MicroRNAs; C000716328:Nr1i3 protein, mouse; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene
keywords: Constitutive androstane receptor; Liver cancer; Mouse; TCPOBOP; microRNA