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

Liu Z, Borlak J, Tong W - Genome Med (2014)

Bottom Line: Comprehensive database searches revealed significantly enriched TFs and miRNAs in CF and CFTR gene networks.STRING analysis confirmed protein-protein interactions (PPIs) among network partners and motif searches defined composite FFLs.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079 USA.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Protein-protein interaction networks of CF-related miRNA. A total of 7 CF regulated miRNAs were used to predict gene targets by employing a total of 10 different algorithms. This defined 263 putative targets which were mapped to the STRING database version 9.1 and revealed 247 PPI among 138 gene targets. Only PPI interaction for homo sapiens were considered and a confidence score >0.4 was requested. The predicted 138 gene targets were mapped to 1,042 DEGs identified among three independent CF patient-related whole genome gene expression data sets. This identified seven genes in common and a total of 19 PPI.
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Fig5: Protein-protein interaction networks of CF-related miRNA. A total of 7 CF regulated miRNAs were used to predict gene targets by employing a total of 10 different algorithms. This defined 263 putative targets which were mapped to the STRING database version 9.1 and revealed 247 PPI among 138 gene targets. Only PPI interaction for homo sapiens were considered and a confidence score >0.4 was requested. The predicted 138 gene targets were mapped to 1,042 DEGs identified among three independent CF patient-related whole genome gene expression data sets. This identified seven genes in common and a total of 19 PPI.

Mentions: Subsequently, we considered disease regulated miRNA and its directionality based on CF patient samples and therefore analyzed the data of Oglesby et al. [40] and Bhattacharyya et al. [41] with respect to the composite FFLs. This revealed a total of seven miRNAs (hsa-miR-26b, hsa-miR-29c, hsa-miR-135b, hsa-miR-155, hsa-miR-192, hsa-miR-200c, and hsa-miR-340) and nine FFLs to be CF associated. Note, in the case of miR-155 three different TFs are involved, that is, SP1, NFKB1, and EBF1, therefore giving rise to three distinct disease-relevant FFLs. We considered miRNAs whose expression was either increased or decreased in CF patient samples (see Figure 4). In order to predict targets of disease associated FFLs we employed a consensus approach using 10 different algorithms (see Additional file 6: Figure S3). The predicted gene targets were considered positive only when confirmed by at least eight different algorithms. Apart from disease specific miRNAs that were used to construct FFLs the regulation of target genes was also considered in CF patient samples. As described above we compiled a total of 1,042 DEGs derived from GEO submissions GSE2395, GSE55146, and GSE15568, and observed DEGs to be commonly regulated in CF samples and disease-specific FFLs, once again providing evidence for the clinical relevance (see Figure 5)Figure 4


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

Liu Z, Borlak J, Tong W - Genome Med (2014)

Protein-protein interaction networks of CF-related miRNA. A total of 7 CF regulated miRNAs were used to predict gene targets by employing a total of 10 different algorithms. This defined 263 putative targets which were mapped to the STRING database version 9.1 and revealed 247 PPI among 138 gene targets. Only PPI interaction for homo sapiens were considered and a confidence score >0.4 was requested. The predicted 138 gene targets were mapped to 1,042 DEGs identified among three independent CF patient-related whole genome gene expression data sets. This identified seven genes in common and a total of 19 PPI.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4256829&req=5

Fig5: Protein-protein interaction networks of CF-related miRNA. A total of 7 CF regulated miRNAs were used to predict gene targets by employing a total of 10 different algorithms. This defined 263 putative targets which were mapped to the STRING database version 9.1 and revealed 247 PPI among 138 gene targets. Only PPI interaction for homo sapiens were considered and a confidence score >0.4 was requested. The predicted 138 gene targets were mapped to 1,042 DEGs identified among three independent CF patient-related whole genome gene expression data sets. This identified seven genes in common and a total of 19 PPI.
Mentions: Subsequently, we considered disease regulated miRNA and its directionality based on CF patient samples and therefore analyzed the data of Oglesby et al. [40] and Bhattacharyya et al. [41] with respect to the composite FFLs. This revealed a total of seven miRNAs (hsa-miR-26b, hsa-miR-29c, hsa-miR-135b, hsa-miR-155, hsa-miR-192, hsa-miR-200c, and hsa-miR-340) and nine FFLs to be CF associated. Note, in the case of miR-155 three different TFs are involved, that is, SP1, NFKB1, and EBF1, therefore giving rise to three distinct disease-relevant FFLs. We considered miRNAs whose expression was either increased or decreased in CF patient samples (see Figure 4). In order to predict targets of disease associated FFLs we employed a consensus approach using 10 different algorithms (see Additional file 6: Figure S3). The predicted gene targets were considered positive only when confirmed by at least eight different algorithms. Apart from disease specific miRNAs that were used to construct FFLs the regulation of target genes was also considered in CF patient samples. As described above we compiled a total of 1,042 DEGs derived from GEO submissions GSE2395, GSE55146, and GSE15568, and observed DEGs to be commonly regulated in CF samples and disease-specific FFLs, once again providing evidence for the clinical relevance (see Figure 5)Figure 4

Bottom Line: Comprehensive database searches revealed significantly enriched TFs and miRNAs in CF and CFTR gene networks.STRING analysis confirmed protein-protein interactions (PPIs) among network partners and motif searches defined composite FFLs.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079 USA.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus