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Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis

BACKGROUND: Cystic fibrosis (CF) is a fatal genetic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that primarily affects the lungs and the digestive system, and the current drug treatment is mainly able to alleviate symptoms. To improve disease management for...

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Autores principales: Liu, Zhichao, Borlak, Jürgen, Tong, Weida
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256829/
https://www.ncbi.nlm.nih.gov/pubmed/25484921
http://dx.doi.org/10.1186/s13073-014-0094-2
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author Liu, Zhichao
Borlak, Jürgen
Tong, Weida
author_facet Liu, Zhichao
Borlak, Jürgen
Tong, Weida
author_sort Liu, Zhichao
collection PubMed
description BACKGROUND: Cystic fibrosis (CF) is a fatal genetic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that primarily affects the lungs and the digestive system, and the current drug treatment is mainly able to alleviate symptoms. To improve disease management for CF, we considered the repurposing of approved drugs and hypothesized that specific microRNA (miRNA) transcription factors (TF) gene networks can be used to generate feed-forward loops (FFLs), thus providing treatment opportunities on the basis of disease specific FFLs. METHODS: Comprehensive database searches revealed significantly enriched TFs and miRNAs in CF and CFTR gene networks. The target genes were validated using ChIPBase and by employing a consensus approach of diverse algorithms to predict miRNA gene targets. STRING analysis confirmed protein-protein interactions (PPIs) among network partners and motif searches defined composite FFLs. Using information extracted from SM2miR and Pharmaco-miR, an in silico drug repurposing pipeline was established based on the regulation of miRNA/TFs in CF/CFTR networks. RESULTS: In human airway epithelium, a total of 15 composite FFLs were constructed based on CFTR specific miRNA/TF gene networks. Importantly, nine of them were confirmed in patient samples and CF epithelial cells lines, and STRING PPI analysis provided evidence that the targets interacted with each other. Functional analysis revealed that ubiquitin-mediated proteolysis and protein processing in the endoplasmic reticulum dominate the composite FFLs, whose major functions are folding, sorting, and degradation. Given that the mutated CFTR gene disrupts the function of the chloride channel, the constructed FFLs address mechanistic aspects of the disease and, among 48 repurposing drug candidates, 26 were confirmed with literature reports and/or existing clinical trials relevant to the treatment of CF patients. CONCLUSION: The construction of FFLs identified promising drug repurposing candidates for CF and the developed strategy may be applied to other diseases as well. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-014-0094-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-42568292014-12-05 Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis Liu, Zhichao Borlak, Jürgen Tong, Weida Genome Med Research BACKGROUND: Cystic fibrosis (CF) is a fatal genetic disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that primarily affects the lungs and the digestive system, and the current drug treatment is mainly able to alleviate symptoms. To improve disease management for CF, we considered the repurposing of approved drugs and hypothesized that specific microRNA (miRNA) transcription factors (TF) gene networks can be used to generate feed-forward loops (FFLs), thus providing treatment opportunities on the basis of disease specific FFLs. METHODS: Comprehensive database searches revealed significantly enriched TFs and miRNAs in CF and CFTR gene networks. The target genes were validated using ChIPBase and by employing a consensus approach of diverse algorithms to predict miRNA gene targets. STRING analysis confirmed protein-protein interactions (PPIs) among network partners and motif searches defined composite FFLs. Using information extracted from SM2miR and Pharmaco-miR, an in silico drug repurposing pipeline was established based on the regulation of miRNA/TFs in CF/CFTR networks. RESULTS: In human airway epithelium, a total of 15 composite FFLs were constructed based on CFTR specific miRNA/TF gene networks. Importantly, nine of them were confirmed in patient samples and CF epithelial cells lines, and STRING PPI analysis provided evidence that the targets interacted with each other. Functional analysis revealed that ubiquitin-mediated proteolysis and protein processing in the endoplasmic reticulum dominate the composite FFLs, whose major functions are folding, sorting, and degradation. Given that the mutated CFTR gene disrupts the function of the chloride channel, the constructed FFLs address mechanistic aspects of the disease and, among 48 repurposing drug candidates, 26 were confirmed with literature reports and/or existing clinical trials relevant to the treatment of CF patients. CONCLUSION: The construction of FFLs identified promising drug repurposing candidates for CF and the developed strategy may be applied to other diseases as well. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13073-014-0094-2) contains supplementary material, which is available to authorized users. BioMed Central 2014-12-02 /pmc/articles/PMC4256829/ /pubmed/25484921 http://dx.doi.org/10.1186/s13073-014-0094-2 Text en © Liu et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Liu, Zhichao
Borlak, Jürgen
Tong, Weida
Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis
title Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis
title_full Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis
title_fullStr Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis
title_full_unstemmed Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis
title_short Deciphering miRNA transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis
title_sort deciphering mirna transcription factor feed-forward loops to identify drug repurposing candidates for cystic fibrosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256829/
https://www.ncbi.nlm.nih.gov/pubmed/25484921
http://dx.doi.org/10.1186/s13073-014-0094-2
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