Genes regulated by the same miRNA can be
discovered by virtue of their co-expression at the transcriptional level and
the presence of a conserved miRNA-binding site in their 3’ UTRs. Using this principle we
have integrated the three best performing and complementary algorithms into a
framework for inference of regulation by miRNAs (FIRM) from sets of
co-expressed genes. We demonstrate the utility of FIRM by inferring a
cancer-miRNA regulatory network through the analysis of 2,240 gene
co-expression signatures from 46 cancers.
By analyzing this network for functional enrichment of known hallmarks
of cancer we have discovered a subset of 13 miRNAs that regulate oncogenic
processes across diverse cancers. We
have performed experiments to test predictions from this miRNA-regulatory
network to demonstrate that miRNAs of the miR-29 family (miR-29a, miR-29b and
miR-29c) regulate specific genes associated with tissue invasion and metastasis
in lung adenocarcinoma. Further, we
highlight the specificity of using FIRM inferences to identify miRNA regulated
genes by experimentally validating that miR-767-5p, which partially shares the
miR-29 seed sequence, regulates only a subset of miR-29 targets. By providing mechanistic linkage between
miRNA dysregulation in cancer, their binding sites in the 3’UTRs of specific
sets of co-expressed genes, and their associations with known hallmarks of
cancer, FIRM and the inferred cancer miRNA-regulatory network will serve as a
powerful public resource for discovery of potential cancer biomarkers.
Source : A miRNA-regulatory network explains how dysregulated miRNAs perturb
oncogenic processes across diverse cancers. Christopher L Plaisier, Min Pan and
Nitin S Baliga (nbaliga@systemsbiology.org).
Genome Res. 2012 Jun 28
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