title: Identifying dysfunctional miRNA-mRNA regulatory modules by inverse activation, cofunction, and high interconnection of target genes: a case study of glioblastoma.
abstract: BACKGROUND
  Accumulating evidence demonstrates that complex diseases may arise from cooperative effects of multiple dysfunctional miRNAs. Thus, identifying abnormal functions cooperatively regulated by multiple miRNAs is useful for understanding the pathogenesis of complex diseases.
  
  
  METHODS
  In this study, we proposed a multistep method to identify dysfunctional miRNA-mRNA regulatory modules (dMiMRMs) in a specific disease, in which a group of miRNAs cooperatively regulate a group of target genes involved in a specific function. We identified dysfunctional miRNAs, which were differentially expressed and inversely regulated most of their target genes, by integrating paired miRNA and mRNA expression profiles and miRNA target information. Then, we identified cooperative functional units, in each of which a pair of miRNAs cooperatively repressed function-enriched and highly interconnected target genes. Finally, the cooperative functional units were assembled into dMiMRMs.
  
  
  RESULTS
  We applied our method to glioblastoma (GBM) and identified GBM-associated dMiMRMs at the population, subtype, and individual levels. We identified 5 common dMiMRMs using all GBM samples, 3 of which were associated with the prognosis in patients with GBM and were better predictors of prognosis than were miRNAs or mRNAs alone. By applying our approach to GBM subtypes, we found consistent dMiMRMs across GBM subtypes, and some subtype-specific dMiMRMs were observed. Furthermore, personalized dMiMRMs were identified, suggesting significant individual differences in different patients with GBM.
  
  
  CONCLUSIONS
  Our method provides the capability to identify miRNA-mediated dysfunctional mechanisms underlying complex diseases.
authors.affiliation: College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xiao
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Ping
authors.forename: Huihui
authors.initials: H
authors.lastname: Fan
authors.forename: Chaohan
authors.initials: C
authors.lastname: Xu
authors.forename: Jinxia
authors.initials: J
authors.lastname: Guan
authors.forename: Hongying
authors.initials: H
authors.lastname: Zhao
authors.forename: Yiqun
authors.initials: Y
authors.lastname: Li
authors.forename: Yanling
authors.initials: Y
authors.lastname: Lv
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Lihua
authors.initials: L
authors.lastname: Wang
authors.forename: Xia
authors.initials: X
authors.lastname: Li
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D019295:Computational Biology; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000145:classification / Q000235:genetics* / Q000401:mortality; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics*; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; D012333:RNA, Messenger
keywords: cooperation; glioblastoma; miRNA and mRNA expression profiles; miRNA-mRNA regulatory module