title: Identification of rifampin-regulated functional modules and related microRNAs in human hepatocytes based on the protein interaction network.
abstract: In combination with gene expression profiles, the protein interaction network (PIN) constructs a dynamic network that includes multiple functional modules. Previous studies have demonstrated that rifampin can influence drug metabolism by regulating drug-metabolizing enzymes, transporters, and microRNAs (miRNAs). Rifampin induces gene expression, at least in part, by activating the pregnane X receptor (PXR), which induces gene expression; however, the impact of rifampin on global gene regulation has not been examined under the molecular network frameworks.
  
  
  
  In this study, we extracted rifampin-induced significant differentially expressed genes (SDG) based on the gene expression profile. By integrating the SDG and human protein interaction network (HPIN), we constructed the rifampin-regulated protein interaction network (RrPIN). Based on gene expression measurements, we extracted a subnetwork that showed enriched changes in molecular activity. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG), we identified the crucial rifampin-regulated biological pathways and associated genes. In addition, genes targeted by miRNAs that were significantly differentially expressed in the miRNA expression profile were extracted based on the miRNA-gene prediction tools. The miRNA-regulated PIN was further constructed using associated genes and miRNAs. For each miRNA, we further evaluated the potential impact by the gene interaction network using pathway analysis. RESULTS AND DISCCUSSION: We extracted the functional modules, which included 84 genes and 89 interactions, from the RrPIN, and identified 19 key rifampin-response genes that are associated with seven function pathways that include drug response and metabolism, and cancer pathways; many of the pathways were supported by previous studies. In addition, we identified that a set of 6 genes (CAV1, CREBBP, SMAD3, TRAF2, KBKG, and THBS1) functioning as gene hubs in the subnetworks that are regulated by rifampin. It is also suggested that 12 differentially expressed miRNAs were associated with 6 biological pathways.
  
  
  
  Our results suggest that rifampin contributes to changes in the expression of genes by regulating key molecules in the protein interaction networks. This study offers valuable insights into rifampin-induced biological mechanisms at the level of miRNAs, genes and proteins.
authors.affiliation: College of Automation, Harbin Engineering University, 145 Nantong Street, Nangang District, Harbin, Heilongjiang, 150001, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Automation, Harbin Engineering University, 145 Nantong Street, Nangang District, Harbin, Heilongjiang, 150001, China.|Network Information Center, Qiqihar University, No.42, Wenhua Street, Qiqihar, Heilongjiang, 161006, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: College of Automation, Harbin Engineering University, 145 Nantong Street, Nangang District, Harbin, Heilongjiang, 150001, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Network Information Center, Qiqihar University, No.42, Wenhua Street, Qiqihar, Heilongjiang, 161006, China.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Dai
authors.affiliation: College of Automation, Harbin Engineering University, 145 Nantong Street, Nangang District, Harbin, Heilongjiang, 150001, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Cong
authors.affiliation: College of Automation, Harbin Engineering University, 145 Nantong Street, Nangang District, Harbin, Heilongjiang, 150001, China.
authors.forename: Weixing
authors.initials: W
authors.lastname: Feng
authors.affiliation: College of Automation, Harbin Engineering University, 145 Nantong Street, Nangang District, Harbin, Heilongjiang, 150001, China.
authors.forename: Chengzhen
authors.initials: C
authors.lastname: Xu
authors.affiliation: College of Automation, Harbin Engineering University, 145 Nantong Street, Nangang District, Harbin, Heilongjiang, 150001, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Skaar
authors.affiliation: College of Automation, Harbin Engineering University, 145 Nantong Street, Nangang District, Harbin, Heilongjiang, 150001, China. lh@hrbeu.edu.cn.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA. lh@hrbeu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Liang
authors.affiliation: College of Automation, Harbin Engineering University, 145 Nantong Street, Nangang District, Harbin, Heilongjiang, 150001, China. yunliu@iupui.edu.|Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. yunliu@iupui.edu.|Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA. yunliu@iupui.edu.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000904:Antibiotics, Antitubercular / Q000627:therapeutic use; D019295:Computational Biology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics; D046228:Microarray Analysis; D000077297:Pregnane X Receptor; D060066:Protein Interaction Maps / Q000187:drug effects / Q000235:genetics*; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000235:genetics; D012293:Rifampin / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000904:Antibiotics, Antitubercular; D035683:MicroRNAs; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D012293:Rifampin