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MicroRNAs act complementarily to regulate disease-related mRNA modules in human diseases

Journal article
Authors Sreenivas Chavali
Sören Bruhn
K. Tiemann
P. Saetrom
Fredrik Barrenäs
T. Saito
Kartiek Kanduri
Hui Wang
Mikael Benson
Published in Rna-a Publication of the Rna Society
Volume 19
Issue 11
Pages 1552-1562
ISSN 1355-8382
Publication year 2013
Published at Institute of Clinical Sciences, Department of Pediatrics
Pages 1552-1562
Language en
Links dx.doi.org/10.1261/rna.038414.113
https://gup.ub.gu.se/file/116191
Keywords microRNA, diseases, regulation, modules, NETWORK-BASED ANALYSIS, PROTEIN COMPLEXES, EXPRESSION, TARGETS, PREDICTION, DISORDERS, RESPONSES, CANCER, GENES, CELLS
Subject categories Biochemistry and Molecular Biology

Abstract

MicroRNAs (miRNAs) play a key role in regulating mRNA expression, and individual miRNAs have been proposed as diagnostic and therapeutic candidates. The identification of such candidates is complicated by the involvement of multiple miRNAs and mRNAs as well as unknown disease topology of the miRNAs. Here, we investigated if disease-associated miRNAs regulate modules of disease-associated mRNAs, if those miRNAs act complementarily or synergistically, and if single or combinations of miRNAs can be targeted to alter module functions. We first analyzed publicly available miRNA and mRNA expression data for five different diseases. Integrated target prediction and network-based analysis showed that the miRNAs regulated modules of disease-relevant genes. Most of the miRNAs acted complementarily to regulate multiple mRNAs. To functionally test these findings, we repeated the analysis using our own miRNA and mRNA expression data from CD4+ T cells from patients with seasonal allergic rhinitis. This is a good model of complex diseases because of its well-defined phenotype and pathogenesis. Combined computational and functional studies confirmed that miRNAs mainly acted complementarily and that a combination of two complementary miRNAs, miR-223 and miR-139-3p, could be targeted to alter disease-relevant module functions, namely, the release of type 2 helper T-cell (Th2) cytokines. Taken together, our findings indicate that miRNAs act complementarily to regulate modules of disease-related mRNAs and can be targeted to alter disease-relevant functions.

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