Identification of a gene signature for discriminating metastatic from primary melanoma using a molecular interaction network approach.

Understanding the biological factors that are characteristic of metastasis in melanoma remains a key approach to improving treatment. In this study, we seek to identify a gene signature of metastatic melanoma. We configured a new network-based computational pipeline, combined with a machine learning method, to mine publicly available transcriptomic data from melanoma patient samples. Our method is unbiased and scans a genome-wide protein-protein interaction network using a novel formulation for network scoring. Using this, we identify the most influential, differentially expressed nodes in metastatic as compared to primary melanoma. We evaluated the shortlisted genes by a machine learning method to rank them by their discriminatory capacities. From this, we identified a panel of 6 genes, ALDH1A1, HSP90AB1, KIT, KRT16, SPRR3 and TMEM45B whose expression values discriminated metastatic from primary melanoma (87% classification accuracy). In an independent transcriptomic data set derived from 703 primary melanomas, we showed that all six genes were significant in predicting melanoma specific survival (MSS) in a univariate analysis, which was also consistent with AJCC staging. Further, 3 of these genes, HSP90AB1, SPRR3 and KRT16 remained significant predictors of MSS in a joint analysis (HR = 2.3, P = 0.03) although, HSP90AB1 (HR = 1.9, P = 2 × 10-4) alone remained predictive after adjusting for clinical predictors.

DenHunt - A Comprehensive Database of the Intricate Network of Dengue-Human Interactions.

Dengue virus (DENV) is a human pathogen and its etiology has been widely established. There are many interactions between DENV and human proteins that have been reported in literature. However, no publicly accessible resource for efficiently retrieving the information is yet available. In this study, we mined all publicly available dengue-human interactions that have been reported in the literature into a database called DenHunt. We retrieved 682 direct interactions of human proteins with dengue viral components, 382 indirect interactions and 4120 differentially expressed human genes in dengue infected cell lines and patients. We have illustrated the importance of DenHunt by mapping the dengue-human interactions on to the host interactome and observed that the virus targets multiple host functional complexes of important cellular processes such as metabolism, immune system and signaling pathways suggesting a potential role of these interactions in viral pathogenesis. We also observed that 7 percent of the dengue virus interacting human proteins are also associated with other infectious and non-infectious diseases. Finally, the understanding that comes from such analyses could be used to design better strategies to counteract the diseases caused by dengue virus. The whole dataset has been catalogued in a searchable database, called DenHunt (http://proline.biochem.iisc.ernet.in/DenHunt/).

SInCRe-structural interactome computational resource for Mycobacterium tuberculosis.

We have developed an integrated database for Mycobacterium tuberculosis H37Rv (Mtb) that collates information on protein sequences, domain assignments, functional annotation and 3D structural information along with protein-protein and protein-small molecule interactions. SInCRe (Structural Interactome Computational Resource) is developed out of CamBan (Cambridge and Bangalore) collaboration. The motivation for development of this database is to provide an integrated platform to allow easily access and interpretation of data and results obtained by all the groups in CamBan in the field of Mtb informatics. In-house algorithms and databases developed independently by various academic groups in CamBan are used to generate Mtb-specific datasets and are integrated in this database to provide a structural dimension to studies on tuberculosis. The SInCRe database readily provides information on identification of functional domains, genome-scale modelling of structures of Mtb proteins and characterization of the small-molecule binding sites within Mtb. The resource also provides structure-based function annotation, information on small-molecule binders including FDA (Food and Drug Administration)-approved drugs, protein-protein interactions (PPIs) and natural compounds that bind to pathogen proteins potentially and result in weakening or elimination of host-pathogen protein-protein interactions. Together they provide prerequisites for identification of off-target binding.

Structure-based barcoding of proteins.

A reduced representation in the format of a barcode has been developed to provide an overview of the topological nature of a given protein structure from 3D coordinate file. The molecular structure of a protein coordinate file from Protein Data Bank is first expressed in terms of an alpha-numero code and further converted to a barcode image. The barcode representation can be used to compare and contrast different proteins based on their structure. The utility of this method has been exemplified by comparing structural barcodes of proteins that belong to same fold family, and across different folds. In addition to this, we have attempted to provide an illustration to (i) the structural changes often seen in a given protein molecule upon interaction with ligands and (ii) Modifications in overall topology of a given protein during evolution. The program is fully downloadable from the website http://www.iitg.ac.in/probar/.

Mycobacterium tuberculosis and Clostridium difficille interactomes: demonstration of rapid development of computational system for bacterial interactome prediction.

BACKGROUND: Protein-protein interaction (PPI) networks (interactomes) of most organisms, except for some model organisms, are largely unknown. Experimental methods including high-throughput techniques are highly resource intensive. Therefore, computational discovery of PPIs can accelerate biological discovery by presenting "most-promising" pairs of proteins that are likely to interact. For many bacteria, genome sequence, and thereby genomic context of proteomes, is readily available; additionally, for some of these proteomes, localization and functional annotations are also available, but interactomes are not available. We present here a method for rapid development of computational system to predict interactome of bacterial proteomes. While other studies have presented methods to transfer interologs across species, here, we propose transfer of computational models to benefit from cross-species annotations, thereby predicting many more novel interactions even in the absence of interologs. Mycobacterium tuberculosis (Mtb) and Clostridium difficile (CD) have been used to demonstrate the work. RESULTS: We developed a random forest classifier over features derived from Gene Ontology annotations and genetic context scores provided by STRING database for predicting Mtb and CD interactions independently. The Mtb classifier gave a precision of 94% and a recall of 23% on a held out test set. The Mtb model was then run on all the 8 million protein pairs of the Mtb proteome, resulting in 708 new interactions (at 94% expected precision) or 1,595 new interactions at 80% expected precision. The CD classifier gave a precision of 90% and a recall of 16% on a held out test set. The CD model was run on all the 8 million protein pairs of the CD proteome, resulting in 143 new interactions (at 90% expected precision) or 580 new interactions (at 80% expected precision). We also compared the overlap of predictions of our method with STRING database interactions for CD and Mtb and also with interactions identified recently by a bacterial 2-hybrid system for Mtb. To demonstrate the utility of transfer of computational models, we made use of the developed Mtb model and used it to predict CD protein-pairs. The cross species model thus developed yielded a precision of 88% at a recall of 8%. To demonstrate transfer of features from other organisms in the absence of feature-based and interaction-based information, we transferred missing feature values from Mtb orthologs into the CD data. In transferring this data from orthologs (not interologs), we showed that a large number of interactions can be predicted. CONCLUSIONS: Rapid discovery of (partial) bacterial interactome can be made by using existing set of GO and STRING features associated with the organisms. We can make use of cross-species interactome development, when there are not even sufficient known interactions to develop a computational prediction system. Computational model of well-studied organism(s) can be employed to make the initial interactome prediction for the target organism. We have also demonstrated successfully, that annotations can be transferred from orthologs in well-studied organisms enabling accurate predictions for organisms with no annotations. These approaches can serve as building blocks to address the challenges associated with feature coverage, missing interactions towards rapid interactome discovery for bacterial organisms. AVAILABILITY: The predictions for all Mtb and CD proteins are made available at: http://severus.dbmi.pitt.edu/TB and http://severus.dbmi.pitt.edu/CD respectively for browsing as well as for download.