title: Integrative analysis of the transcriptome and targetome identifies the regulatory network of miR-16: an inhibitory role against the activation of hepatic stellate cells.
abstract: Hepatic stellate cell (HSC) activation is the critical event of liver fibrosis. Abnormality of miR-16 expression induces their activation. However, the action model of miR-16 remains to be elucidated because of its multiple-targeted manner. Here, we report that miR-16 restoration exerted a wide-range impact on transcriptome (2,082 differentially expressed transcripts) of activated HSCs. Integrative analysis of both targetome (1,195 targets) and transcriptome uncovered the miR-16 regulatory network based upon bio-molecular interaction databases (BIND, BioGrid, Tranfac, and KEGG), cross database searching with iterative algorithm, Dijkstra's algorithm with greedy method, etc. Eight targets in the targetome (Map2k1, Bmpr1b, Nf1, Pik3r3, Ppp2r1a, Prkca, Smad2, and Sos2) served as key regulatory network nodes that mediate miR-16 action. A set of TFs (Sp1, Jun, Crebl, Arnt, Fos, and Nf1) was recognized to be the functional layer of key nodes, which mapped the signal of miR-16 to transcriptome. In result, the comprehensive action of miR-16 abrogated transcriptomic characteristics that determined the phenotypes of activated HSCs, including active proliferation, ECM deposition, and apoptosis resistance. Therefore, a multi-layer regulatory network based upon the integration of targetome and transcriptome may underlie the global action of miR-16, which suggesting it plays an inhibitory role in HSC activation.
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University 200092, 1665 Kong Jiang Rd., Shanghai, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Digestive Disease Laboratory and Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University 200001, 2000 Jiang Yue Rd., Shanghai, China.
authors.forename: Canjie
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University 200092, 1665 Kong Jiang Rd., Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University 200092, 1665 Kong Jiang Rd., Shanghai, China Shanghai Key Laboratory of Children' s Digestion and Nutrition 200092, 1665 Kong Jiang Rd., Shanghai, China.
authors.forename: Jiangao
authors.initials: J
authors.lastname: Fan
authors.affiliation: School of Electronics and Information Engineering, Tong Ji University, 201804, 4800 Cao An Rd., Shanghai, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Fang
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000502:physiology*; D018390:Gene Targeting; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D059467:Transcriptome / Q000235:genetics*
chemical_list: C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors
keywords: hepatic stellate cell; miR-16; network; targetome; transcriptome