Predicting molecular mechanisms of hereditary diseases by using their tissue-selective manifestation.

How do aberrations in widely expressed genes lead to tissue-selective hereditary diseases? Previous attempts to answer this question were limited to testing a few candidate mechanisms. To answer this question at a larger scale, we developed "Tissue Risk Assessment of Causality by Expression" (TRACE), a machine learning approach to predict genes that underlie tissue-selective diseases and selectivity-related features. TRACE utilized 4,744 biologically interpretable tissue-specific gene features that were inferred from heterogeneous omics datasets. Application of TRACE to 1,031 disease genes uncovered known and novel selectivity-related features, the most common of which was previously overlooked. Next, we created a catalog of tissue-associated risks for 18,927 protein-coding genes (https://netbio.bgu.ac.il/trace/). As proof-of-concept, we prioritized candidate disease genes identified in 48 rare-disease patients. TRACE ranked the verified disease gene among the patient's candidate genes significantly better than gene prioritization methods that rank by gene constraint or tissue expression. Thus, tissue selectivity combined with machine learning enhances genetic and clinical understanding of hereditary diseases.

ProAct: quantifying the differential activity of biological processes in tissues, cells, and user-defined contexts.

The distinct functions and phenotypes of human tissues and cells derive from the activity of biological processes that varies in a context-dependent manner. Here, we present the Process Activity (ProAct) webserver that estimates the preferential activity of biological processes in tissues, cells, and other contexts. Users can upload a differential gene expression matrix measured across contexts or cells, or use a built-in matrix of differential gene expression in 34 human tissues. Per context, ProAct associates gene ontology (GO) biological processes with estimated preferential activity scores, which are inferred from the input matrix. ProAct visualizes these scores across processes, contexts, and process-associated genes. ProAct also offers potential cell-type annotations for cell subsets, by inferring them from the preferential activity of 2001 cell-type-specific processes. Thus, ProAct output can highlight the distinct functions of tissues and cell types in various contexts, and can enhance cell-type annotation efforts. The ProAct webserver is available at https://netbio.bgu.ac.il/ProAct/.

The TissueNet v.3 Database: Protein-protein Interactions in Adult and Embryonic Human Tissue contexts.

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.

The differential activity of biological processes in tissues and cell subsets can illuminate disease-related processes and cell-type identities.

MOTIVATION: The distinct functionalities of human tissues and cell types underlie complex phenotype-genotype relationships, yet often remain elusive. Harnessing the multitude of bulk and single-cell human transcriptomes while focusing on processes can help reveal these distinct functionalities. RESULTS: The Tissue-Process Activity (TiPA) method aims to identify processes that are preferentially active or under-expressed in specific contexts, by comparing the expression levels of process genes between contexts. We tested TiPA on 1579 tissue-specific processes and bulk tissue transcriptomes, finding that it performed better than another method. Next, we used TiPA to ask whether the activity of certain processes could underlie the tissue-specific manifestation of 1233 hereditary diseases. We found that 21% of the disease-causing genes indeed participated in such processes, thereby illuminating their genotype-phenotype relationships. Lastly, we applied TiPA to single-cell transcriptomes of 108 human cell types, revealing that process activities often match cell-type identities and can thus aid annotation efforts. Hence, differential activity of processes can highlight the distinct functionality of tissues and cells in a robust and meaningful manner. AVAILABILITY AND IMPLEMENTATION: TiPA code is available in GitHub (https://github.com/moranshar/TiPA). In addition, all data are available as part of the Supplementary Material. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Role of duplicate genes in determining the tissue-selectivity of hereditary diseases.

A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues, while their causal genes are expressed throughout the human body. A general conception is that tissue-selective disease phenotypes emerge when masking factors operate in unaffected tissues, but are specifically absent or insufficient in disease-manifesting tissues. Although this conception has critical impact on the understanding of disease manifestation, it was never challenged in a systematic manner across a variety of hereditary diseases and affected tissues. Here, we address this gap in our understanding via rigorous analysis of the susceptibility of over 30 tissues to 112 tissue-selective hereditary diseases. We focused on the roles of paralogs of causal genes, which are presumably capable of compensating for their aberration. We show for the first time at large-scale via quantitative analysis of omics datasets that, preferentially in the disease-manifesting tissues, paralogs are under-expressed relative to causal genes in more than half of the diseases. This was observed for several susceptible tissues and for causal genes with varying number of paralogs, suggesting that imbalanced expression of paralogs increases tissue susceptibility. While for many diseases this imbalance stemmed from up-regulation of the causal gene in the disease-manifesting tissue relative to other tissues, it was often combined with down-regulation of its paralog. Notably in roughly 20% of the cases, this imbalance stemmed only from significant down-regulation of the paralog. Thus, dosage relationships between paralogs appear as important, yet currently under-appreciated, modifiers of disease manifestation.

The TissueNet v.2 database: A quantitative view of protein-protein interactions across human tissues.

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 crosstalk between IL-22 signaling and miR-197 in human keratinocytes.

The interaction between the immune system and epithelial cells is tightly regulated. Aberrations of this balance may result in inflammatory diseases such as psoriasis, inflammatory bowel disease and rheumatoid arthritis. IL-22 is produced by Th17, Th22 and Th1 cells. Putative targets for IL-22 are cells in the skin, kidney, digestive and respiratory systems. The highest expression of IL-22 receptor is found in the skin. IL-22 plays an important role in the pathogenesis of T cell-mediated inflammatory diseases such as psoriasis, inflammatory bowel disease and rheumatoid arthritis. Recently, we found that miR-197 is down regulated in psoriatic lesions. In the present work we show that miR-197 over expression inhibits keratinocytes proliferation induced by IL-22 and keratinocytes migration. In addition, we found that IL-22 activates miR-197 expression through the binding of phosphorylated STAT3 to sequences in the putative promoter of miR-197. Finally we found that IL-22 receptor subunit IL22RA1 is a direct target of miR-197. Hence, we identified a novel feedback loop controlling IL-22 signaling, in which IL-22 induces miR-197, which in turn, negatively regulates IL-22 receptor and attenuates the biological outcome of such signaling. Regulation of this pathway may be important in inflammatory skin disorders such a psoriasis and in wound healing.