Identification of microRNA-regulated gene networks by expression analysis of target genes

Abstract

MicroRNAs (miRNAs) and transcription factors control eukaryotic cell proliferation, differentiation, and metabolism through their specific gene regulatory networks. However, differently from transcription factors, our understanding of the processes regulated by miRNAs is currently limited. Here, we introduce gene network analysis as a new means for gaining insight into miRNA biology. A systematic analysis of all human miRNAs based on Co-expression Meta-analysis of miRNA Targets (CoMeTa) assigns high-resolution biological functions to miRNAs and provides a comprehensive, genome-scale analysis of human miRNA regulatory networks. Moreover, gene cotargeting analyses show that miRNAs synergistically regulate cohorts of genes that participate in similar processes. We experimentally validate the CoMeTa procedure through focusing on three poorly characterized miRNAs, miR-519d/190/340, which CoMeTa predicts to be associated with the TGFb pathway. Using lung adenocarcinoma A549 cells as a model system, we show that miR-519d and miR-190 inhibit, while miR-340 enhances TGFb signaling and its effects on cell proliferation, morphology, and scattering. Based on these findings, we formalize and propose co-expression analysis as a general paradigm for second-generation procedures to recognize bona fide targets and infer biological roles and network communities of miRNAs.

Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p

“…A single miRNA or group of miRNAs can regulate a specific biological pathway by modulating the expression of various proteins participating in the same pathway (Gennarino et al 2012). To understand the major functional pathway regulated by miR-483-5p, we ran cooperational level (COOL) analysis (Gennarino et al 2012) followed by gene ontology (GO) analysis for miR-483-5p.…”

“…To understand the major functional pathway regulated by miR-483-5p, we ran cooperational level (COOL) analysis (Gennarino et al 2012) followed by gene ontology (GO) analysis for miR-483-5p. COOL analysis clusters the putative targets of specific miRNA based on the highest degree of coexpression (Gennarino et al 2012). Interestingly, the COOL and GO analysis for miR-483-5p showed enrichment of chromatinrelated functions ( Fig.…”

“…To this end, we used a newly developed bioinformatic tool-coexpression meta-analysis of miRNA targets (CoMeTa)-that predicts and ranks human miRNA target mRNAs based on their expression relationships (Gennarino et al 2012). CoMeTa predicted six miRNAs for human MECP2 (Fig.…”

Anti-CD38 Antibody Therapy: Windows of Opportunity Yielded by the Functional Characteristics of the Target Molecule

“…Similar analysis performed by testing miRNAs has shown a reproducible increase of miR33a-5p and miR-340-5p, whereas miR-193-5p and miR-629-3p are decreased. The induced miRNAs share the ability to influence signals involved in proliferation, cell cycle progression and migration (33,35,61). In any case, the safety issue is maintained and the limited number of miRNAs mobilized also may represent a beneficial effect.…”

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

“…For these reasons, miRNAs are currently known as powerful regulators of gene expression. One miRNA has the ability to interact with many target mRNAs and to regulate their expression (Gennarino et al., 2012; Helwak et al., 2013; Hendrickson et al., 2009; Tsang, Ebert & van Oudenaarden, 2010). Currently, 64% of the human miRNAs belong to seed families, which correspond to microRNAs sharing the same or a highly similar seed region (Kozomara & Griffiths‐Jones, 2011).…”