Identification of rifampin-regulated functional modules and related microRNAs in human hepatocytes based on the protein interaction network

Abstract

BackgroundIn 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.MethodsIn 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 DisccussionWe 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2909-6) contains supplementary material, which is available to authorized users.

MicroRNA Mediated Changes in Drug Metabolism and Target Gene Expression by Efavirenz and Rifampicin In Vitro: Clinical Implications

“…We identified that 10 microRNAs were upregulated, and 13 microRNAs were downregulated after treatment with 24.4 μM RMP. Several previous studies investigated the effects of RMP on microRNA expression in hepatocytes and HepaRG cells (Benson et al, 2016; Li et al, 2015, 2016; Ramamoorthy et al, 2013; Smith et al, 2014; Yan et al, 2017). In the study by Yan et al (2017), HepaRG cells were treated with 10 μM RMP and the expression of 18 microRNAs was increased, whereas the expression of 72 microRNAs was decreased.…”

Intelligent biology and medicine in 2015: advancing interdisciplinary education, collaboration, and data science

“…In addition, many top predictions have been demonstrated effective in inhibiting the growth of human GBM cells. In [19], Li et al extracted the functional modules and identified 19 key rifampinresponse genes that are associated with seven function pathways that include drug response and metabolism, and cancer pathways. In addition, six genes functioning as gene hubs in the gene networks that are regulated by rifampin was identified.…”