miRDRN-miRNA disease regulatory network: a tool for exploring disease and tissue-specific microRNA regulatory networks.

BACKGROUND: MicroRNA (miRNA) regulates cellular processes by acting on specific target genes, and cellular processes proceed through multiple interactions often organized into pathways among genes and gene products. Hundreds of miRNAs and their target genes have been identified, as are many miRNA-disease associations. These, together with huge amounts of data on gene annotation, biological pathways, and protein-protein interactions are available in public databases. Here, using such data we built a database and web service platform, miRNA disease regulatory network (miRDRN), for users to construct disease and tissue-specific miRNA-protein regulatory networks, with which they may explore disease related molecular and pathway associations, or find new ones, and possibly discover new modes of drug action. METHODS: Data on disease-miRNA association, miRNA-target association and validation, gene-tissue association, gene-tumor association, biological pathways, human protein interaction, gene ID, gene ontology, gene annotation, and product were collected from publicly available databases and integrated. A large set of miRNA target-specific regulatory sub-pathways (RSPs) having the form (T, G 1, G 2) was built from the integrated data and stored, where T is a miRNA-associated target gene, G 1 (G 2) is a gene/protein interacting with T (G 1). Each sequence (T, G 1, G 2) was assigned a p-value weighted by the participation of the three genes in molecular interactions and reaction pathways. RESULTS: A web service platform, miRDRN (http://mirdrn.ncu.edu.tw/mirdrn/), was built. The database part of miRDRN currently stores 6,973,875 p-valued RSPs associated with 116 diseases in 78 tissue types built from 207 diseases-associated miRNA regulating 389 genes. miRDRN also provides facilities for the user to construct disease and tissue-specific miRNA regulatory networks from RSPs it stores, and to download and/or visualize parts or all of the product. User may use miRDRN to explore a single disease, or a disease-pair to gain insights on comorbidity. As demonstrations, miRDRN was applied: to explore the single disease colorectal cancer (CRC), in which 26 novel potential CRC target genes were identified; to study the comorbidity of the disease-pair Alzheimer's disease-Type 2 diabetes, in which 18 novel potential comorbid genes were identified; and, to explore possible causes that may shed light on recent failures of late-phase trials of anti-AD, BACE1 inhibitor drugs, in which genes downstream to BACE1 whose suppression may affect signal transduction were identified.

Gene-Set Local Hierarchical Clustering (GSLHC)--A Gene Set-Based Approach for Characterizing Bioactive Compounds in Terms of Biological Functional Groups.

Gene-set-based analysis (GSA), which uses the relative importance of functional gene-sets, or molecular signatures, as units for analysis of genome-wide gene expression data, has exhibited major advantages with respect to greater accuracy, robustness, and biological relevance, over individual gene analysis (IGA), which uses log-ratios of individual genes for analysis. Yet IGA remains the dominant mode of analysis of gene expression data. The Connectivity Map (CMap), an extensive database on genomic profiles of effects of drugs and small molecules and widely used for studies related to repurposed drug discovery, has been mostly employed in IGA mode. Here, we constructed a GSA-based version of CMap, Gene-Set Connectivity Map (GSCMap), in which all the genomic profiles in CMap are converted, using gene-sets from the Molecular Signatures Database, to functional profiles. We showed that GSCMap essentially eliminated cell-type dependence, a weakness of CMap in IGA mode, and yielded significantly better performance on sample clustering and drug-target association. As a first application of GSCMap we constructed the platform Gene-Set Local Hierarchical Clustering (GSLHC) for discovering insights on coordinated actions of biological functions and facilitating classification of heterogeneous subtypes on drug-driven responses. GSLHC was shown to tightly clustered drugs of known similar properties. We used GSLHC to identify the therapeutic properties and putative targets of 18 compounds of previously unknown characteristics listed in CMap, eight of which suggest anti-cancer activities. The GSLHC website http://cloudr.ncu.edu.tw/gslhc/ contains 1,857 local hierarchical clusters accessible by querying 555 of the 1,309 drugs and small molecules listed in CMap. We expect GSCMap and GSLHC to be widely useful in providing new insights in the biological effect of bioactive compounds, in drug repurposing, and in function-based classification of complex diseases.

ncRNAppi--a tool for identifying disease-related miRNA and siRNA targeting pathways.

UNLABELLED: Currently, there are a number of databases which store microRNA (miRNA) information, and tools available which provide miRNA target prediction. In this article, we describe a novel web-based tool that integrate the miRNA-targeted mRNA data, protein-protein interactions (PPI) records, tissues, biochemical pathways, human disease and gene function information to establish a disease-related miRNA target pathway database. This database is unique in the sense that it links miRNA target genes with their PPI partners according to being tissue- and diseases-specific or both. The same approach is also applied to siRNA data. This database provides two types of searches: (i) tissue- and (ii) disease-specific miRNA (or siRNA) targeting pathways. The search allows one to identify tissue- or disease-specific miRNA (or siRNA) target gene's PPI partners two levels beyond. AVAILABILITY: The release version 1.0 is a freely accessible database available at http://ncrnappi.cs.nthu.edu.tw and http://ncRNAppi.bioinfo.asia.edu.tw/.

Applications of domain-domain interactions in pathway study.

The domain combination pair approach is employed to derive putative protein domain-domain interactions (DDI) from the protein-protein interactions (PPI) database DIP. The results of putative DDI are computed for seven species. To determine the prediction performance, putative DDI results are compared with that of the database InterDom, where an average matching ratio of about 76% can be achieved. Several real PPI pathways are reconstructed based on the predicted DDI results. It is found that the pathways could be reconstructed with reasonable accuracy. Furthermore, a novel quantity, so called AP-order index, is introduced to predict the regulatory order for six PPI pathways. It is found that the AP-order index is a very reliable parameter to determine the regulatory order of PPI.