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1.
Cell ; 177(6): 1375-1383, 2019 05 30.
Article in English | MEDLINE | ID: mdl-31150618

ABSTRACT

Recent studies of the tumor genome seek to identify cancer pathways as groups of genes in which mutations are epistatic with one another or, specifically, "mutually exclusive." Here, we show that most mutations are mutually exclusive not due to pathway structure but to interactions with disease subtype and tumor mutation load. In particular, many cancer driver genes are mutated preferentially in tumors with few mutations overall, causing mutations in these cancer genes to appear mutually exclusive with numerous others. Researchers should view current epistasis maps with caution until we better understand the multiple cause-and-effect relationships among factors such as tumor subtype, positive selection for mutations, and gross tumor characteristics including mutational signatures and load.


Subject(s)
Epistasis, Genetic/genetics , Genes, Neoplasm/genetics , Neoplasms/genetics , Algorithms , Computational Biology/methods , Epistasis, Genetic/physiology , Genes, Neoplasm/physiology , Humans , Models, Genetic , Mutation/genetics , Oncogenes/genetics
2.
Cell ; 177(3): 572-586.e22, 2019 04 18.
Article in English | MEDLINE | ID: mdl-30955884

ABSTRACT

Drug resistance and relapse remain key challenges in pancreatic cancer. Here, we have used RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and genome-wide CRISPR analysis to map the molecular dependencies of pancreatic cancer stem cells, highly therapy-resistant cells that preferentially drive tumorigenesis and progression. This integrated genomic approach revealed an unexpected utilization of immuno-regulatory signals by pancreatic cancer epithelial cells. In particular, the nuclear hormone receptor retinoic-acid-receptor-related orphan receptor gamma (RORγ), known to drive inflammation and T cell differentiation, was upregulated during pancreatic cancer progression, and its genetic or pharmacologic inhibition led to a striking defect in pancreatic cancer growth and a marked improvement in survival. Further, a large-scale retrospective analysis in patients revealed that RORγ expression may predict pancreatic cancer aggressiveness, as it positively correlated with advanced disease and metastasis. Collectively, these data identify an orthogonal co-option of immuno-regulatory signals by pancreatic cancer stem cells, suggesting that autoimmune drugs should be evaluated as novel treatment strategies for pancreatic cancer patients.


Subject(s)
Adenocarcinoma/pathology , Neoplastic Stem Cells/metabolism , Pancreatic Neoplasms/pathology , Adenocarcinoma/genetics , Adenocarcinoma/metabolism , Animals , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Cell Differentiation , Epigenesis, Genetic , Gene Library , Humans , Mice , Mice, Knockout , Mice, SCID , Neoplastic Stem Cells/cytology , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , RNA Interference , RNA, Small Interfering/metabolism , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Receptors, Interleukin-10/antagonists & inhibitors , Receptors, Interleukin-10/genetics , Receptors, Interleukin-10/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Transcriptome , Tumor Cells, Cultured
3.
Cell ; 173(7): 1562-1565, 2018 06 14.
Article in English | MEDLINE | ID: mdl-29906441

ABSTRACT

A major ambition of artificial intelligence lies in translating patient data to successful therapies. Machine learning models face particular challenges in biomedicine, however, including handling of extreme data heterogeneity and lack of mechanistic insight into predictions. Here, we argue for "visible" approaches that guide model structure with experimental biology.


Subject(s)
Computational Biology/methods , Machine Learning , Algorithms , Biomedical Research
4.
Cell ; 174(3): 505-520, 2018 07 26.
Article in English | MEDLINE | ID: mdl-30053424

ABSTRACT

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.


Subject(s)
Chromosome Mapping/methods , Neurodevelopmental Disorders/genetics , Systems Biology/methods , Gene Regulatory Networks/genetics , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Genomics/methods , Humans , Neurobiology/methods , Neuropsychiatry
5.
Cell ; 171(6): 1272-1283.e15, 2017 Nov 30.
Article in English | MEDLINE | ID: mdl-29107334

ABSTRACT

MHC-I molecules expose the intracellular protein content on the cell surface, allowing T cells to detect foreign or mutated peptides. The combination of six MHC-I alleles each individual carries defines the sub-peptidome that can be effectively presented. We applied this concept to human cancer, hypothesizing that oncogenic mutations could arise in gaps in personal MHC-I presentation. To validate this hypothesis, we developed and applied a residue-centric patient presentation score to 9,176 cancer patients across 1,018 recurrent oncogenic mutations. We found that patient MHC-I genotype-based scores could predict which mutations were more likely to emerge in their tumor. Accordingly, poor presentation of a mutation across patients was correlated with higher frequency among tumors. These results support that MHC-I genotype-restricted immunoediting during tumor formation shapes the landscape of oncogenic mutations observed in clinically diagnosed tumors and paves the way for predicting personal cancer susceptibilities from knowledge of MHC-I genotype.


Subject(s)
Antigen Presentation , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Mutation , Neoplasms/immunology , Cell Line, Tumor , Computer Simulation , Female , HeLa Cells , Humans , Male , Monitoring, Immunologic , Proteome
6.
Cell ; 157(3): 534-8, 2014 Apr 24.
Article in English | MEDLINE | ID: mdl-24766803

ABSTRACT

Modern genomics is very efficient at mapping genes and gene networks, but how to transform these maps into predictive models of the cell remains unclear. Recent progress in computer science, embodied by intelligent agents such as Siri, inspires an approach for moving from networks to multiscale models able to predict a range of cellular phenotypes and answer biological questions.


Subject(s)
Artificial Intelligence , Biological Ontologies , Cell Biology , Models, Biological , Cell Biology/trends , Gene Regulatory Networks , Natural Language Processing , Systems Biology
7.
Mol Cell ; 81(12): 2656-2668.e8, 2021 06 17.
Article in English | MEDLINE | ID: mdl-33930332

ABSTRACT

A deficient interferon (IFN) response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been implicated as a determinant of severe coronavirus disease 2019 (COVID-19). To identify the molecular effectors that govern IFN control of SARS-CoV-2 infection, we conducted a large-scale gain-of-function analysis that evaluated the impact of human IFN-stimulated genes (ISGs) on viral replication. A limited subset of ISGs were found to control viral infection, including endosomal factors inhibiting viral entry, RNA binding proteins suppressing viral RNA synthesis, and a highly enriched cluster of endoplasmic reticulum (ER)/Golgi-resident ISGs inhibiting viral assembly/egress. These included broad-acting antiviral ISGs and eight ISGs that specifically inhibited SARS-CoV-2 and SARS-CoV-1 replication. Among the broad-acting ISGs was BST2/tetherin, which impeded viral release and is antagonized by SARS-CoV-2 Orf7a protein. Overall, these data illuminate a set of ISGs that underlie innate immune control of SARS-CoV-2/SARS-CoV-1 infection, which will facilitate the understanding of host determinants that impact disease severity and offer potential therapeutic strategies for COVID-19.


Subject(s)
Antigens, CD/genetics , Host-Pathogen Interactions/genetics , Interferon Regulatory Factors/genetics , Interferon Type I/genetics , SARS-CoV-2/genetics , Viral Proteins/genetics , Animals , Antigens, CD/chemistry , Antigens, CD/immunology , Binding Sites , Cell Line, Tumor , Chlorocebus aethiops , Endoplasmic Reticulum/genetics , Endoplasmic Reticulum/immunology , Endoplasmic Reticulum/virology , GPI-Linked Proteins/chemistry , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunology , Gene Expression Regulation , Golgi Apparatus/genetics , Golgi Apparatus/immunology , Golgi Apparatus/virology , HEK293 Cells , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Interferon Regulatory Factors/classification , Interferon Regulatory Factors/immunology , Interferon Type I/immunology , Molecular Docking Simulation , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/immunology , Signal Transduction , Vero Cells , Viral Proteins/chemistry , Viral Proteins/immunology , Virus Internalization , Virus Release/genetics , Virus Release/immunology , Virus Replication/genetics , Virus Replication/immunology
8.
Cell ; 151(6): 1161-2, 2012 Dec 07.
Article in English | MEDLINE | ID: mdl-23217702

ABSTRACT

An accurate prediction of how extrinsic stimuli influence changes in gene expression has been challenging. In this issue, Nagano and colleagues successfully model genome-wide mRNA expression changes under variable environmental conditions in rice, raising hopes that scientists will soon be able to predict genome-wide transcriptional responses in a variety of organisms in uncontrolled real-world settings.

9.
Cell ; 148(3): 543-55, 2012 Feb 03.
Article in English | MEDLINE | ID: mdl-22304920

ABSTRACT

The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress. The ability of ATF2 to reach the mitochondria is determined by PKCε, which directs ATF2 nuclear localization. Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor samples, high PKCε levels associate with poor prognosis. Overall, our findings provide the framework for understanding how subcellular localization enables ATF2 oncogenic or tumor suppressor functions.


Subject(s)
Activating Transcription Factor 2/metabolism , Apoptosis , Melanoma/metabolism , Mitochondria/metabolism , Protein Kinase C-epsilon/metabolism , Cell Line , Cell Line, Tumor , Cell Nucleus/metabolism , Cytosol/metabolism , DNA Damage , Fibroblasts/metabolism , Hexokinase/metabolism , Humans , Prognosis , Protein Transport , Voltage-Dependent Anion Channel 1/metabolism
10.
Nature ; 600(7889): 536-542, 2021 12.
Article in English | MEDLINE | ID: mdl-34819669

ABSTRACT

The cell is a multi-scale structure with modular organization across at least four orders of magnitude1. Two central approaches for mapping this structure-protein fluorescent imaging and protein biophysical association-each generate extensive datasets, but of distinct qualities and resolutions that are typically treated separately2,3. Here we integrate immunofluorescence images in the Human Protein Atlas4 with affinity purifications in BioPlex5 to create a unified hierarchical map of human cell architecture. Integration is achieved by configuring each approach as a general measure of protein distance, then calibrating the two measures using machine learning. The map, known as the multi-scale integrated cell (MuSIC 1.0), resolves 69 subcellular systems, of which approximately half are to our knowledge undocumented. Accordingly, we perform 134 additional affinity purifications and validate subunit associations for the majority of systems. The map reveals a pre-ribosomal RNA processing assembly and accessory factors, which we show govern rRNA maturation, and functional roles for SRRM1 and FAM120C in chromatin and RPS3A in splicing. By integration across scales, MuSIC increases the resolution of imaging while giving protein interactions a spatial dimension, paving the way to incorporate diverse types of data in proteome-wide cell maps.


Subject(s)
Chromosomes , Proteome , Antigens, Nuclear/genetics , Antigens, Nuclear/metabolism , Chromatin/genetics , Chromosomes/metabolism , Humans , Nuclear Matrix-Associated Proteins/metabolism , Proteome/metabolism , RNA, Ribosomal , RNA-Binding Proteins/genetics
11.
Cell ; 144(6): 860-3, 2011 Mar 18.
Article in English | MEDLINE | ID: mdl-21414478

ABSTRACT

A major difficulty in the analysis of complex biological systems is dealing with the low signal-to-noise inherent to nearly all large biological datasets. We discuss powerful bioinformatic concepts for boosting signal-to-noise through external knowledge incorporated in processing units we call filters and integrators. These concepts are illustrated in four landmark studies that have provided model implementations of filters, integrators, or both.


Subject(s)
Signal Processing, Computer-Assisted , Algorithms , Disease/genetics , Gene Regulatory Networks , Genome, Human , Genome-Wide Association Study , Humans , Proteins/metabolism , Signal Transduction
12.
Mol Cell ; 69(2): 321-333.e3, 2018 01 18.
Article in English | MEDLINE | ID: mdl-29351850

ABSTRACT

We have developed a highly parallel strategy, systematic gene-to-phenotype arrays (SGPAs), to comprehensively map the genetic landscape driving molecular phenotypes of interest. By this approach, a complete yeast genetic mutant array is crossed with fluorescent reporters and imaged on membranes at high density and contrast. Importantly, SGPA enables quantification of phenotypes that are not readily detectable in ordinary genetic analysis of cell fitness. We benchmark SGPA by examining two fundamental biological phenotypes: first, we explore glucose repression, in which SGPA identifies a requirement for the Mediator complex and a role for the CDK8/kinase module in regulating transcription. Second, we examine selective protein quality control, in which SGPA identifies most known quality control factors along with U34 tRNA modification, which acts independently of proteasomal degradation to limit misfolded protein production. Integration of SGPA with other fluorescent readouts will enable genetic dissection of a wide range of biological pathways and conditions.


Subject(s)
High-Throughput Nucleotide Sequencing/methods , High-Throughput Screening Assays/methods , Cyclin-Dependent Kinase 8/genetics , Gene Regulatory Networks , Genotype , Mediator Complex/genetics , Oligonucleotide Array Sequence Analysis , Phenotype , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics
13.
Mol Cell ; 71(6): 882-895, 2018 09 20.
Article in English | MEDLINE | ID: mdl-30241605

ABSTRACT

Age-associated changes to the mammalian DNA methylome are well documented and thought to promote diseases of aging, such as cancer. Recent studies have identified collections of individual methylation sites whose aggregate methylation status measures chronological age, referred to as the DNA methylation clock. DNA methylation may also have value as a biomarker of healthy versus unhealthy aging and disease risk; in other words, a biological clock. Here we consider the relationship between the chronological and biological clocks, their underlying mechanisms, potential consequences, and their utility as biomarkers and as targets for intervention to promote healthy aging and longevity.


Subject(s)
Aging/genetics , Cellular Senescence/genetics , DNA Methylation/genetics , Animals , Biological Clocks/genetics , Cellular Senescence/physiology , CpG Islands/genetics , Epigenesis, Genetic/genetics , Humans , Longevity/genetics
14.
Mol Cell ; 69(2): 306-320.e4, 2018 01 18.
Article in English | MEDLINE | ID: mdl-29351849

ABSTRACT

Endoplasmic reticulum (ER)-associated degradation (ERAD) removes misfolded proteins from the ER membrane and lumen by the ubiquitin-proteasome pathway. Retrotranslocation of ubiquitinated substrates to the cytosol is a universal feature of ERAD that requires the Cdc48 AAA-ATPase. Despite intense efforts, the mechanism of ER exit, particularly for integral membrane (ERAD-M) substrates, has remained unclear. Using a self-ubiquitinating substrate (SUS), which undergoes normal retrotranslocation independently of known ERAD factors, and the new SPOCK (single plate orf compendium kit) micro-library to query all yeast genes, we found the rhomboid derlin Dfm1 was required for retrotranslocation of both HRD and DOA ERAD pathway integral membrane substrates. Dfm1 recruited Cdc48 to the ER membrane with its unique SHP motifs, and it catalyzed substrate extraction through its conserved rhomboid motifs. Surprisingly, dfm1Δ can undergo rapid suppression, restoring wild-type ERAD-M. This unexpected suppression explained earlier studies ruling out Dfm1, and it revealed an ancillary ERAD-M retrotranslocation pathway requiring Hrd1.


Subject(s)
Membrane Proteins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Adenosine Triphosphatases/metabolism , Cell Cycle Proteins/metabolism , Cytosol/metabolism , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum-Associated Degradation/physiology , Membrane Proteins/physiology , Proteasome Endopeptidase Complex/metabolism , Saccharomyces cerevisiae/metabolism , Ubiquitin/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitination , Valosin Containing Protein/metabolism
15.
Mol Cell ; 69(4): 699-708.e7, 2018 02 15.
Article in English | MEDLINE | ID: mdl-29452643

ABSTRACT

The metabolic pathways fueling tumor growth have been well characterized, but the specific impact of transforming events on network topology and enzyme essentiality remains poorly understood. To this end, we performed combinatorial CRISPR-Cas9 screens on a set of 51 carbohydrate metabolism genes that represent glycolysis and the pentose phosphate pathway (PPP). This high-throughput methodology enabled systems-level interrogation of metabolic gene dispensability, interactions, and compensation across multiple cell types. The metabolic impact of specific combinatorial knockouts was validated using 13C and 2H isotope tracing, and these assays together revealed key nodes controlling redox homeostasis along the KEAP-NRF2 signaling axis. Specifically, targeting KEAP1 in combination with oxidative PPP genes mitigated the deleterious effects of these knockouts on growth rates. These results demonstrate how our integrated framework, combining genetic, transcriptomic, and flux measurements, can improve elucidation of metabolic network alterations and guide precision targeting of metabolic vulnerabilities based on tumor genetics.


Subject(s)
CRISPR-Cas Systems , Kelch-Like ECH-Associated Protein 1/metabolism , Metabolic Networks and Pathways , NF-E2-Related Factor 2/metabolism , Transcriptome , Glycolysis , HeLa Cells , Homeostasis , Humans , Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors , Kelch-Like ECH-Associated Protein 1/genetics , NF-E2-Related Factor 2/antagonists & inhibitors , NF-E2-Related Factor 2/genetics , Oxidation-Reduction , Pentose Phosphate Pathway , Signal Transduction
16.
Bioinformatics ; 40(Suppl 1): i160-i168, 2024 06 28.
Article in English | MEDLINE | ID: mdl-38940147

ABSTRACT

MOTIVATION: Predicting cancer drug response requires a comprehensive assessment of many mutations present across a tumor genome. While current drug response models generally use a binary mutated/unmutated indicator for each gene, not all mutations in a gene are equivalent. RESULTS: Here, we construct and evaluate a series of predictive models based on leading methods for quantitative mutation scoring. Such methods include VEST4 and CADD, which score the impact of a mutation on gene function, and CHASMplus, which scores the likelihood a mutation drives cancer. The resulting predictive models capture cellular responses to dabrafenib, which targets BRAF-V600 mutations, whereas models based on binary mutation status do not. Performance improvements generalize to other drugs, extending genetic indications for PIK3CA, ERBB2, EGFR, PARP1, and ABL1 inhibitors. Introducing quantitative mutation features in drug response models increases performance and mechanistic understanding. AVAILABILITY AND IMPLEMENTATION: Code and example datasets are available at https://github.com/pgwall/qms.


Subject(s)
Antineoplastic Agents , Mutation , Neoplasms , Humans , Neoplasms/genetics , Neoplasms/drug therapy , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Imidazoles/pharmacology , Oximes/pharmacology , Computational Biology/methods
17.
Bioinformatics ; 40(Suppl 2): ii105-ii110, 2024 09 01.
Article in English | MEDLINE | ID: mdl-39230695

ABSTRACT

The data deluge in biology calls for computational approaches that can integrate multiple datasets of different types to build a holistic view of biological processes or structures of interest. An emerging paradigm in this domain is the unsupervised learning of data embeddings that can be used for downstream clustering and classification tasks. While such approaches for integrating data of similar types are becoming common, there is scarcer work on consolidating different data modalities such as network and image information. Here, we introduce DICE (Data Integration through Contrastive Embedding), a contrastive learning model for multi-modal data integration. We apply this model to study the subcellular organization of proteins by integrating protein-protein interaction data and protein image data measured in HEK293 cells. We demonstrate the advantage of data integration over any single modality and show that our framework outperforms previous integration approaches. Availability: https://github.com/raminass/protein-contrastive Contact: raminass@gmail.com.


Subject(s)
Computational Biology , Humans , HEK293 Cells , Computational Biology/methods , Protein Interaction Mapping/methods , Proteins/metabolism , Proteins/chemistry , Unsupervised Machine Learning
18.
Cell ; 140(5): 744-52, 2010 Mar 05.
Article in English | MEDLINE | ID: mdl-20211142

ABSTRACT

Combinatorial interactions among transcription factors are critical to directing tissue-specific gene expression. To build a global atlas of these combinations, we have screened for physical interactions among the majority of human and mouse DNA-binding transcription factors (TFs). The complete networks contain 762 human and 877 mouse interactions. Analysis of the networks reveals that highly connected TFs are broadly expressed across tissues, and that roughly half of the measured interactions are conserved between mouse and human. The data highlight the importance of TF combinations for determining cell fate, and they lead to the identification of a SMAD3/FLI1 complex expressed during development of immunity. The availability of large TF combinatorial networks in both human and mouse will provide many opportunities to study gene regulation, tissue differentiation, and mammalian evolution.


Subject(s)
Gene Expression Regulation , Gene Regulatory Networks , Transcription Factors/metabolism , Animals , Cell Differentiation , Evolution, Molecular , Humans , Mice , Monocytes/cytology , Organ Specificity , Smad3 Protein/metabolism , Trans-Activators/metabolism
19.
Mol Cell ; 65(4): 761-774.e5, 2017 Feb 16.
Article in English | MEDLINE | ID: mdl-28132844

ABSTRACT

We have developed a general progressive procedure, Active Interaction Mapping, to guide assembly of the hierarchy of functions encoding any biological system. Using this process, we assemble an ontology of functions comprising autophagy, a central recycling process implicated in numerous diseases. A first-generation model, built from existing gene networks in Saccharomyces, captures most known autophagy components in broad relation to vesicle transport, cell cycle, and stress response. Systematic analysis identifies synthetic-lethal interactions as most informative for further experiments; consequently, we saturate the model with 156,364 such measurements across autophagy-activating conditions. These targeted interactions provide more information about autophagy than all previous datasets, producing a second-generation ontology of 220 functions. Approximately half are previously unknown; we confirm roles for Gyp1 at the phagophore-assembly site, Atg24 in cargo engulfment, Atg26 in cytoplasm-to-vacuole targeting, and Ssd1, Did4, and others in selective and non-selective autophagy. The procedure and autophagy hierarchy are at http://atgo.ucsd.edu/.


Subject(s)
Autophagy/genetics , Gene Regulatory Networks , Genomics/methods , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae/genetics , Systems Biology/methods , Autophagy-Related Proteins/genetics , Autophagy-Related Proteins/metabolism , Databases, Genetic , Endosomal Sorting Complexes Required for Transport/genetics , Endosomal Sorting Complexes Required for Transport/metabolism , GTPase-Activating Proteins/genetics , GTPase-Activating Proteins/metabolism , Gene Expression Regulation, Fungal , Glucosyltransferases/genetics , Glucosyltransferases/metabolism , Humans , Models, Genetic , Pichia/genetics , Pichia/metabolism , Protein Interaction Maps , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Systems Integration
20.
Bioinformatics ; 39(3)2023 03 01.
Article in English | MEDLINE | ID: mdl-36882166

ABSTRACT

MOTIVATION: The investigation of sets of genes using biological pathways is a common task for researchers and is supported by a wide variety of software tools. This type of analysis generates hypotheses about the biological processes that are active or modulated in a specific experimental context. RESULTS: The Network Data Exchange Integrated Query (NDEx IQuery) is a new tool for network and pathway-based gene set interpretation that complements or extends existing resources. It combines novel sources of pathways, integration with Cytoscape, and the ability to store and share analysis results. The NDEx IQuery web application performs multiple gene set analyses based on diverse pathways and networks stored in NDEx. These include curated pathways from WikiPathways and SIGNOR, published pathway figures from the last 27 years, machine-assembled networks using the INDRA system, and the new NCI-PID v2.0, an updated version of the popular NCI Pathway Interaction Database. NDEx IQuery's integration with MSigDB and cBioPortal now provides pathway analysis in the context of these two resources. AVAILABILITY AND IMPLEMENTATION: NDEx IQuery is available at https://www.ndexbio.org/iquery and is implemented in Javascript and Java.


Subject(s)
Computational Biology , Software , Computational Biology/methods , Protein Interaction Maps , Publications , Databases, Factual , Internet
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