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Key Points Network propagation transforms a short list of candidate genes into a genome-wide profile of gene scores that are based on proximity to candidates in a gene network. This transformation greatly improves the power of genetic association, providing a universal amplifier for genetic analysis. Mathematically, the technique of network propagation is simplifying and unifying. Network propagation methods can be used to identify genes and genetic modules that underlie human disease. Network propagation is based on the principle that genes underlying similar phenotypes are more likely to interact with each other. It is proving to be a powerful approach for extracting biological information from molecular networks that is relevant to human disease. Biological networks are powerful resources for the discovery of genes and genetic modules that drive disease. Fundamental to network analysis is the concept that genes underlying the same phenotype tend to interact; this principle can be used to combine and to amplify signals from individual genes. Recently, numerous bioinformatic techniques have been proposed for genetic analysis using networks, based on random walks, information diffusion and electrical resistance. These approaches have been applied successfully to identify disease genes, genetic modules and drug targets. In fact, all these approaches are variations of a unifying mathematical machinery — network propagation — suggesting that it is a powerful data transformation method of broad utility in genetic research.

The protein-protein interaction (PPI) network of an organism serves as a skeleton for its signaling circuitry, which mediates cellular response to environmental and genetic cues. Understanding this circuitry could improve the prediction of gene function and cellular behavior in response to diverse signals. To realize this potential, one has to comprehensively map PPIs and their directions of signal flow. While the quality and the volume of identified human PPIs improved dramatically over the last decade, the directions of these interactions are still mostly unknown, thus precluding subsequent prediction and modeling efforts. Here we present a systematic approach to orient the human PPI network using drug response and cancer genomic data. We provide a diffusion-based method for the orientation task that significantly outperforms existing methods. The oriented network leads to improved prioritization of cancer driver genes and drug targets compared to the state-of-the-art unoriented network. The directions of most human protein-protein interactions (PPIs) remain unknown. Here, the authors use cancer genomic and drug response data to infer the direction of signal flow in the human PPI network and show that the directed network improves drug target and cancer driver gene prioritization.

Although artificial neural networks are powerful classifiers, their internal structures are hard to interpret. In the life sciences, extensive knowledge of cell biology provides an opportunity to design visible neural networks (VNNs) that couple the model's inner workings to those of real systems. Here we develop DCell, a VNN embedded in the hierarchical structure of 2,526 subsystems comprising a eukaryotic cell (http://d-cell.ucsd.edu/). Trained on several million genotypes, DCell simulates cellular growth nearly as accurately as laboratory observations. During simulation, genotypes induce patterns of subsystem activities, enabling in silico investigations of the molecular mechanisms underlying genotype-phenotype associations. These mechanisms can be validated, and many are unexpected; some are governed by Boolean logic. Cumulatively, 80% of the importance for growth prediction is captured by 484 subsystems (21%), reflecting the emergence of a complex phenotype. DCell provides a foundation for decoding the genetics of disease, drug resistance and synthetic life.

A fundamental challenge in human health is the identification of disease-causing genes. Recently, several studies have tackled this challenge via a network-based approach, motivated by the observation that genes causing the same or similar diseases tend to lie close to one another in a network of protein-protein or functional interactions. However, most of these approaches use only local network information in the inference process and are restricted to inferring single gene associations. Here, we provide a global, network-based method for prioritizing disease genes and inferring protein complex associations, which we call PRINCE. The method is based on formulating constraints on the prioritization function that relate to its smoothness over the network and usage of prior information. We exploit this function to predict not only genes but also protein complex associations with a disease of interest. We test our method on gene-disease association data, evaluating both the prioritization achieved and the protein complexes inferred. We show that our method outperforms extant approaches in both tasks. Using data on 1,369 diseases from the OMIM knowledgebase, our method is able (in a cross validation setting) to rank the true causal gene first for 34% of the diseases, and infer 139 disease-related complexes that are highly coherent in terms of the function, expression and conservation of their member proteins. Importantly, we apply our method to study three multi-factorial diseases for which some causal genes have been found already: prostate cancer, alzheimer and type 2 diabetes mellitus. PRINCE's predictions for these diseases highly match the known literature, suggesting several novel causal genes and protein complexes for further investigation.

Inferring potential drug indications, for either novel or approved drugs, is a key step in drug development. Previous computational methods in this domain have focused on either drug repositioning or matching drug and disease gene expression profiles. Here, we present a novel method for the large‐scale prediction of drug indications (PREDICT) that can handle both approved drugs and novel molecules. Our method is based on the observation that similar drugs are indicated for similar diseases, and utilizes multiple drug–drug and disease–disease similarity measures for the prediction task. On cross‐validation, it obtains high specificity and sensitivity (AUC=0.9) in predicting drug indications, surpassing existing methods. We validate our predictions by their overlap with drug indications that are currently under clinical trials, and by their agreement with tissue‐specific expression information on the drug targets. We further show that disease‐specific genetic signatures can be used to accurately predict drug indications for new diseases (AUC=0.92). This lays the computational foundation for future personalized drug treatments, where gene expression signatures from individual patients would replace the disease‐specific signatures. Synopsis Predicting indications for new molecules or finding alternative indications for approved drugs is a laborious and costly process (DiMasi et al , 2003 ), calling for computational solutions that would minimize production time and development costs (Terstappen and Reggiani, 2001 ). Here, we present a novel method for predicting drug indications, PREDICT, capable of handling both approved drugs and novel molecules. Our method is based on the assumption that similar drugs are indicated for similar diseases. To score a possible drug–disease association, we compute its similarity to known associations by combining drug–drug and disease–disease similarity computations. This strategy achieves high specificity and sensitivity rates in a cross‐validation setting, where part of the known associations are hidden and the method is assessed based on how well it can retrieve them based on the rest of the associations. Assessing its predictions of novel indications for existing drugs, we find that it covers a significant portion (27%, P <2 × 10 −220 ) of drug indications currently tested on clinical trials. Examples of such predictions include: (i) Cabergoline, indicated for Hyperprolactinemia, which is predicted to treat Migrane, a prediction supported by two separate studies (Verhelst et al , 1999 ; Cavestro et al , 2006 ) and (ii) Progesterone, which is predicted to treat renal cell cancer, non‐papillary (npRCC), supported by the study of Izumi et al (2007) . In addition, we provide indication predictions for novel molecules. For example, Cycloleucine is predicted for the treatment of Alzheimer's disease (AD); indeed, Cycloleucine was found to be a potent and selective antagonist of NMDA receptor‐mediated responses (Hershkowitz and Rogawski, 1989 ), a new promising class of chemicals for the treatment of AD (Farlow, 2004 ). As another example, Hyperforin, St John's wort extract, is predicted to treat hyperthermia. Interestingly, St John's wort extract was found to have anxiolytic effects on stress‐induced hyperthermia in mice (Grundmann et al , 2006 ). We further introduce a disease–disease similarity measure based on disease‐specific gene signatures and show that such a measure can be used by our method to accurately predict drug indications. Importantly, this suggests the potential utility of our approach also in a personalized medicine setting, whereby future gene expression signatures from individual patients would replace these disease‐specific signatures. We present a novel method for the large‐scale prediction of drug indications that can handle both approved drugs and novel molecules. Our method utilizes multiple drug–drug and disease–disease similarity measures for the prediction task, obtaining high specificity and sensitivity rates (AUC=0.9). Our drug repositioning predictions cover 27% of the indications currently tested on clinical trials ( P <2 × 10 −220 ). We show comparable performance using a gene expression signature‐based disease–disease similarity, laying the computational foundation for predicting patient‐specific indications.

Severe acute respiratory syndrome (SARS)-CoV-2 infection leads to severe disease associated with cytokine storm, vascular dysfunction, coagulation, and progressive lung damage. It affects several vital organs, seemingly through a pathological effect on endothelial cells. The SARS-CoV-2 genome encodes 29 proteins, whose contribution to the disease manifestations, and especially endothelial complications, is unknown. We cloned and expressed 26 of these proteins in human cells and characterized the endothelial response to overexpression of each, individually. Whereas most proteins induced significant changes in endothelial permeability, nsp2, nsp5_c145a (catalytic dead mutant of nsp5), and nsp7 also reduced CD31, and increased von Willebrand factor expression and IL-6, suggesting endothelial dysfunction. Using propagation-based analysis of a protein–protein interaction (PPI) network, we predicted the endothelial proteins affected by the viral proteins that potentially mediate these effects. We further applied our PPI model to identify the role of each SARS-CoV-2 protein in other tissues affected by coronavirus disease (COVID-19). While validating the PPI network model, we found that the tight junction (TJ) proteins cadherin-5, ZO-1, and β-catenin are affected by nsp2, nsp5_c145a, and nsp7 consistent with the model prediction. Overall, this work identifies the SARS-CoV-2 proteins that might be most detrimental in terms of endothelial dysfunction, thereby shedding light on vascular aspects of COVID-19.

Inferring drug–drug interactions (DDIs) is an essential step in drug development and drug administration. Most computational inference methods focus on modeling drug pharmacokinetics, aiming at interactions that result from a common metabolizing enzyme (CYP). Here, we introduce a novel prediction method, INDI (INferring Drug Interactions), allowing the inference of both pharmacokinetic, CYP‐related DDIs (along with their associated CYPs) and pharmacodynamic, non‐CYP associated ones. On cross validation, it obtains high specificity and sensitivity levels (AUC (area under the receiver‐operating characteristic curve)⩾0.93). In application to the FDA adverse event reporting system, 53% of the drug events could potentially be connected to known (41%) or predicted (12%) DDIs. Additionally, INDI predicts the severity level of each DDI upon co‐administration of the involved drugs, suggesting that severe interactions are abundant in the clinical practice. Examining regularly taken medications by hospitalized patients, 18% of the patients receive known or predicted severely interacting drugs and are hospitalized more frequently. Access to INDI and its predictions is provided via a web tool at http://www.cs.tau.ac.il/∼bnet/software/INDI , facilitating the inference and exploration of drug interactions and providing important leads for physicians and pharmaceutical companies alike. INDI is a similarity‐based drug–drug interaction prediction method that can infer both pharmacokinetic and pharmacodynamic interactions, as well as their severity levels. Both known and predicted drug interactions are found to be prevalent in clinical practice. Synopsis INDI is a similarity‐based drug–drug interaction prediction method that can infer both pharmacokinetic and pharmacodynamic interactions, as well as their severity levels. Both known and predicted drug interactions are found to be prevalent in clinical practice. INDI is a similarity‐based drug–drug interaction prediction method, capable of handling both pharmacokinetic and pharmacodynamic interactions. INDI predicts the severity of the interaction and the Cytochrome P450 isozyme involved in pharmacokinetic interactions. We show the prevalence of known and predicted drug interactions in drug adverse reports and in chronic medications taken by hospitalized patients.

The Warburg effect--a classical hallmark of cancer metabolism--is a counter-intuitive phenomenon in which rapidly proliferating cancer cells resort to inefficient ATP production via glycolysis leading to lactate secretion, instead of relying primarily on more efficient energy production through mitochondrial oxidative phosphorylation, as most normal cells do. The causes for the Warburg effect have remained a subject of considerable controversy since its discovery over 80 years ago, with several competing hypotheses. Here, utilizing a genome-scale human metabolic network model accounting for stoichiometric and enzyme solvent capacity considerations, we show that the Warburg effect is a direct consequence of the metabolic adaptation of cancer cells to increase biomass production rate. The analysis is shown to accurately capture a three phase metabolic behavior that is observed experimentally during oncogenic progression, as well as a prominent characteristic of cancer cells involving their preference for glutamine uptake over other amino acids.

Development of high-throughput monitoring technologies enables interrogation of cancer samples at various levels of cellular activity. Capitalizing on these developments, various public efforts such as The Cancer Genome Atlas (TCGA) generate disparate omic data for large patient cohorts. As demonstrated by recent studies, these heterogeneous data sources provide the opportunity to gain insights into the molecular changes that drive cancer pathogenesis and progression. However, these insights are limited by the vast search space and as a result low statistical power to make new discoveries. In this paper, we propose methods for integrating disparate omic data using molecular interaction networks, with a view to gaining mechanistic insights into the relationship between molecular changes at different levels of cellular activity. Namely, we hypothesize that genes that play a role in cancer development and progression may be implicated by neither frequent mutation nor differential expression, and that network-based integration of mutation and differential expression data can reveal these \"silent players\". For this purpose, we utilize network-propagation algorithms to simulate the information flow in the cell at a sample-specific resolution. We then use the propagated mutation and expression signals to identify genes that are not necessarily mutated or differentially expressed genes, but have an essential role in tumor development and patient outcome. We test the proposed method on breast cancer and glioblastoma multiforme data obtained from TCGA. Our results show that the proposed method can identify important proteins that are not readily revealed by molecular data, providing insights beyond what can be gleaned by analyzing different types of molecular data in isolation.

Background Robustness and evolutionary stability of gene expression in the human genome are established by an array of redundant enhancers. Results Using Hi-C data in multiple cell lines, we report a comprehensive map of promoters and active enhancers connected by chromatin contacts, spanning 9000 enhancer chains in 4 human cell lines associated with 2600 human genes. We find that the first enhancer in a chain that directly contacts the target promoter is commonly located at a greater genomic distance from the promoter than the second enhancer in a chain, 96 kb vs. 45 kb, respectively. The first enhancer also features higher similarity to the promoter in terms of tissue specificity and higher enrichment of loop factors, suggestive of a stable primary contact with the promoter. In contrast, a chain of enhancers which connects to the target promoter through a neutral DNA segment instead of an enhancer is associated with a significant decrease in target gene expression, suggesting an important role of the first enhancer in initiating transcription using the target promoter and bridging the promoter with other regulatory elements in the locus. Conclusions The widespread chained structure of gene enhancers in humans reveals that the primary, critical enhancer is distal, commonly located further away than other enhancers. This first, distal enhancer establishes contacts with multiple regulatory elements and safeguards a complex regulatory program of its target gene.