TY - JOUR
T1 - Identification of microRNA-regulated gene networks by expression analysis of target genes
AU - Gennarino, Vincenzo Alessandro
AU - D'Angelo, Giovanni
AU - Dharmalingam, Gopuraja
AU - Fernandez, Serena
AU - Russolillo, Giorgio
AU - Sanges, Remo
AU - Mutarelli, Margherita
AU - Belcastro, Vincenzo
AU - Ballabio, Andrea
AU - Verde, Pasquale
AU - Sardiello, Marco
AU - Banfi, Sandro
PY - 2012/6
Y1 - 2012/6
N2 - 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 TGFβ pathway. Using lung adenocarcinoma A549 cells as a model system, we show that miR-519d and miR-190 inhibit, while miR-340 enhances TGFβ 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.
AB - 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 TGFβ pathway. Using lung adenocarcinoma A549 cells as a model system, we show that miR-519d and miR-190 inhibit, while miR-340 enhances TGFβ 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.
UR - http://www.scopus.com/inward/record.url?scp=84861909720&partnerID=8YFLogxK
U2 - 10.1101/gr.130435.111
DO - 10.1101/gr.130435.111
M3 - Article
C2 - 22345618
AN - SCOPUS:84861909720
SN - 1088-9051
VL - 22
SP - 1163
EP - 1172
JO - Genome research
JF - Genome research
IS - 6
ER -