Database Commons

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Tissue contexts are extremely valuable when studying protein functions and their associated phenotypes. Recently, the study of proteins in tissue contexts was greatly facilitated by the availability of thousands of tissue transcriptomes. To provide access to these data we developed the TissueNet integrative database that displays protein-protein interactions (PPIs) in tissue contexts. Through TissueNet, users can create tissue-sensitive network views of the PPI landscape of query proteins. Unlike other tools, TissueNet output networks highlight tissue-specific and broadly expressed proteins, as well as over- and under-expressed proteins per tissue. The TissueNet v.3 upgrade has a much larger dataset of proteins and PPIs, and represents 125 adult tissues and seven embryonic tissues. Thus, TissueNet provides an extensive, quantitative, and user-friendly interface to study the roles of human proteins in adulthood and embryonic stages. TissueNet v3 is freely available at https://netbio.bgu.ac.il/tissuenet3.

Knowledge of the molecular interactions of human proteins within tissues is important for identifying their tissue-specific roles and for shedding light on tissue phenotypes. However, many protein-protein interactions (PPIs) have no tissue-contexts. The TissueNet database bridges this gap by associating experimentally-identified PPIs with human tissues that were shown to express both pair-mates. Users can select a protein and a tissue, and obtain a network view of the query protein and its tissue-associated PPIs. TissueNet v.2 is an updated version of the TissueNet database previously featured in NAR. It includes over 40 human tissues profiled via RNA-sequencing or protein-based assays. Users can select their preferred expression data source and interactively set the expression threshold for determining tissue-association. The output of TissueNet v.2 emphasizes qualitative and quantitative features of query proteins and their PPIs. The tissue-specificity view highlights tissue-specific and globally-expressed proteins, and the quantitative view highlights proteins that were differentially expressed in the selected tissue relative to all other tissues. Together, these views allow users to quickly assess the unique versus global functionality of query proteins. Thus, TissueNet v.2 offers an extensive, quantitative and user-friendly interface to study the roles of human proteins across tissues. TissueNet v.2 is available at http://netbio.bgu.ac.il/tissuenet. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

An open question in human genetics is what underlies the tissue-specific manifestation of hereditary diseases, which are caused by genomic aberrations that are present in cells across the human body. Here we analyzed this phenomenon for over 300 hereditary diseases by using comparative network analysis. We created an extensive resource of protein expression and interactions in 16 main human tissues, by integrating recent data of gene and protein expression across tissues with data of protein-protein interactions (PPIs). The resulting tissue interaction networks (interactomes) shared a large fraction of their proteins and PPIs, and only a small fraction of them were tissue-specific. Applying this resource to hereditary diseases, we first show that most of the disease-causing genes are widely expressed across tissues, yet, enigmatically, cause disease phenotypes in few tissues only. Upon testing for factors that could lead to tissue-specific vulnerability, we find that disease-causing genes tend to have elevated transcript levels and increased number of tissue-specific PPIs in their disease tissues compared to unaffected tissues. We demonstrate through several examples that these tissue-specific PPIs can highlight disease mechanisms, and thus, owing to their small number, provide a powerful filter for interrogating disease etiologies. As two thirds of the hereditary diseases are associated with these factors, comparative tissue analysis offers a meaningful and efficient framework for enhancing the understanding of the molecular basis of hereditary diseases.

Knowledge of protein-protein interactions (PPIs) is important for identifying the functions of proteins and the processes they are involved in. Although data of human PPIs are easily accessible through several public databases, these databases do not specify the human tissues in which these PPIs take place. The TissueNet database of human tissue PPIs (http://netbio.bgu.ac.il/tissuenet/) associates each interaction with human tissues that express both pair mates. This was achieved by integrating current data of experimentally detected PPIs with extensive data of gene and protein expression across 16 main human tissues. Users can query TissueNet using a protein and retrieve its PPI partners per tissue, or using a PPI and retrieve the tissues expressing both pair mates. The graphical representation of the output highlights tissue-specific and tissue-wide PPIs. Thus, TissueNet provides a unique platform for assessing the roles of human proteins and their interactions across tissues.