{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T16:46:18Z","timestamp":1772383578975,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010181","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000}}],"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T00:00:00Z","timestamp":1653955200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R00GM108865"],"award-info":[{"award-number":["R00GM108865"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM103712"],"award-info":[{"award-number":["GM103712"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The high-level organization of the cell is embedded in indirect relationships that connect distinct cellular processes. Existing computational approaches for detecting indirect relationships between genes typically consist of propagating abstract information through network representations of the cell. However, the selection of genes to serve as the source of propagation is inherently biased by prior knowledge. Here, we sought to derive an unbiased view of the high-level organization of the cell by identifying the genes that propagate and receive information most effectively in the cell, and the indirect relationships between these genes. To this aim, we adapted a perturbation-response scanning strategy initially developed for identifying allosteric interactions within proteins. We deployed this strategy onto an elastic network model of the yeast genetic interaction profile similarity network. This network revealed a superior propensity for information propagation relative to simulated networks with similar topology. Perturbation-response scanning identified the major distributors and receivers of information in the network, named effector and sensor genes, respectively. Effectors formed dense clusters centrally integrated into the network, whereas sensors formed loosely connected antenna-shaped clusters and contained genes with previously characterized involvement in signal transduction. We propose that indirect relationships between effector and sensor clusters represent major paths of information flow between distinct cellular processes. Genetic similarity networks for fission yeast and human displayed similarly strong propensities for information propagation and clusters of effector and sensor genes, suggesting that the global architecture enabling indirect relationships is evolutionarily conserved across species. Our results demonstrate that elastic network modeling of cellular networks constitutes a promising strategy to probe the high-level organization and cooperativity in the cell.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010181","type":"journal-article","created":{"date-parts":[[2022,5,31]],"date-time":"2022-05-31T13:40:40Z","timestamp":1654004440000},"page":"e1010181","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Elastic network modeling of cellular networks unveils sensor and effector genes that control information flow"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5361-256X","authenticated-orcid":true,"given":"Omer","family":"Acar","sequence":"first","affiliation":[]},{"given":"She","family":"Zhang","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9959-4176","authenticated-orcid":true,"given":"Ivet","family":"Bahar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6474-6413","authenticated-orcid":true,"given":"Anne-Ruxandra","family":"Carvunis","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,5,31]]},"reference":[{"key":"pcbi.1010181.ref001","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrg1272","article-title":"Network biology: understanding the cell\u2019s functional organization","volume":"5","author":"A-L Barab\u00e1si","year":"2004","journal-title":"Nat Rev Genet"},{"key":"pcbi.1010181.ref002","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1093\/bioinformatics\/btp551","article-title":"How and when should interactome-derived clusters be used to predict functional modules and protein function?","volume":"25","author":"J Song","year":"2009","journal-title":"Bioinformatics"},{"key":"pcbi.1010181.ref003","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1093\/bioinformatics\/btq076","article-title":"The power of protein interaction networks for associating genes with diseases","volume":"26","author":"S Navlakha","year":"2010","journal-title":"Bioinformatics"},{"key":"pcbi.1010181.ref004","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1126\/science.1180823","article-title":"The Genetic Landscape of a Cell","volume":"327","author":"M Costanzo","year":"2010","journal-title":"Science"},{"key":"pcbi.1010181.ref005","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/msb4100129","article-title":"Network-based prediction of protein function","volume":"3","author":"R Sharan","year":"2007","journal-title":"Mol Syst Biol"},{"key":"pcbi.1010181.ref006","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/j.febslet.2009.03.001","article-title":"A network medicine approach to human disease","volume":"583","author":"A Zanzoni","year":"2009","journal-title":"FEBS Lett"},{"key":"pcbi.1010181.ref007","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/nbt1096","article-title":"Systematic interpretation of genetic interactions using protein networks","volume":"23","author":"R Kelley","year":"2005","journal-title":"Nat Biotechnol"},{"key":"pcbi.1010181.ref008","doi-asserted-by":"crossref","first-page":"e1000065","DOI":"10.1371\/journal.pcbi.1000065","article-title":"Functional Maps of Protein Complexes from Quantitative Genetic Interaction Data.","volume":"4","author":"S Bandyopadhyay","year":"2008","journal-title":"PLoS Comput Biol."},{"key":"pcbi.1010181.ref009","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1517\/14622416.2.3.203","article-title":"Genomics complexity and drug discovery: insights from Boolean network models of cellular regulation","volume":"2","author":"S. Huang","year":"2001","journal-title":"Pharmacogenomics"},{"key":"pcbi.1010181.ref010","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrg.2017.38","article-title":"Network propagation: a universal amplifier of genetic associations","volume":"18","author":"L Cowen","year":"2017","journal-title":"Nat Rev Genet"},{"key":"pcbi.1010181.ref011","doi-asserted-by":"crossref","first-page":"7432","DOI":"10.1073\/pnas.0500896102","article-title":"Geometric diffusions as a tool for harmonic analysis and structure definition of data: multiscale methods","volume":"102","author":"RR Coifman","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"pcbi.1010181.ref012","doi-asserted-by":"crossref","first-page":"16090","DOI":"10.1073\/pnas.0905547106","article-title":"Detecting intrinsic slow variables in stochastic dynamical systems by anisotropic diffusion maps","volume":"106","author":"A Singer","year":"2009","journal-title":"Proc Natl Acad Sci USA"},{"key":"pcbi.1010181.ref013","first-page":"506","volume-title":"Algorithms for Detecting Significantly Mutated Pathways in Cancer","author":"F Vandin","year":"2010"},{"key":"pcbi.1010181.ref014","first-page":"55","article-title":"Discovery of mutated subnetworks associated with clinical data in cancer","author":"F Vandin","year":"2012","journal-title":"Pac Symp Biocomput"},{"key":"pcbi.1010181.ref015","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/ng.3168","article-title":"Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes","volume":"47","author":"MDM Leiserson","year":"2015","journal-title":"Nat Genet"},{"key":"pcbi.1010181.ref016","doi-asserted-by":"crossref","first-page":"e172","DOI":"10.1371\/journal.pcbi.0030172","article-title":"Signal Propagation in Proteins and Relation to Equilibrium Fluctuations.","volume":"3","author":"C Chennubhotla","year":"2007","journal-title":"PLOS Comput Biol"},{"key":"pcbi.1010181.ref017","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.ajhg.2008.02.013","article-title":"Walking the Interactome for Prioritization of Candidate Disease Genes","volume":"82","author":"S K\u00f6hler","year":"2008","journal-title":"Am J Hum Genet"},{"key":"pcbi.1010181.ref018","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1186\/1752-0509-8-S1-S6","article-title":"Identifying disease associated genes by network propagation","volume":"8","author":"Y Qian","year":"2014","journal-title":"BMC Syst Biol"},{"key":"pcbi.1010181.ref019","doi-asserted-by":"crossref","first-page":"5119","DOI":"10.1111\/j.1742-4658.2005.04947.x","article-title":"Identifying remote protein homologs by network propagation.","volume":"272","author":"WS Noble","year":"2005","journal-title":"FEBS J"},{"key":"pcbi.1010181.ref020","doi-asserted-by":"crossref","first-page":"e1000544","DOI":"10.1371\/journal.pcbi.1000544","article-title":"Perturbation-Response Scanning Reveals Ligand Entry-Exit Mechanisms of Ferric Binding Protein.","volume":"5","author":"C Atilgan","year":"2009","journal-title":"PLOS Comput Biol."},{"key":"pcbi.1010181.ref021","doi-asserted-by":"crossref","first-page":"e1003624","DOI":"10.1371\/journal.pcbi.1003624","article-title":"ATPase subdomain IA is a mediator of interdomain allostery in Hsp70 molecular chaperones.","volume":"10","author":"IJ General","year":"2014","journal-title":"PLoS Comput Biol"},{"key":"pcbi.1010181.ref022","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.bpj.2010.05.020","article-title":"Manipulation of conformational change in proteins by single-residue perturbations","volume":"99","author":"C Atilgan","year":"2010","journal-title":"Biophys J"},{"key":"pcbi.1010181.ref023","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1359-0278(97)00024-2","article-title":"Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential","volume":"2","author":"I Bahar","year":"1997","journal-title":"Folding and Design"},{"key":"pcbi.1010181.ref024","doi-asserted-by":"crossref","first-page":"3663","DOI":"10.1093\/nar\/gkx172","article-title":"Chromosomal dynamics predicted by an elastic network model explains genome-wide accessibility and long-range couplings","volume":"45","author":"N Sauerwald","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010181.ref025","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"P Shannon","year":"2003","journal-title":"Genome Res"},{"key":"pcbi.1010181.ref026","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.cels.2016.04.014","article-title":"Systematic Functional Annotation and Visualization of Biological Networks","volume":"2","author":"A. Baryshnikova","year":"2016","journal-title":"Cell Syst"},{"key":"pcbi.1010181.ref027","first-page":"353","article-title":"A global genetic interaction network maps a wiring diagram of cellular function","author":"M Costanzo","year":"2016","journal-title":"Science"},{"key":"pcbi.1010181.ref028","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/nature08454","article-title":"Molecular networks as sensors and drivers of common human diseases","volume":"461","author":"EE Schadt","year":"2009","journal-title":"Nature"},{"key":"pcbi.1010181.ref029","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1126\/science.1091317","article-title":"Global mapping of the yeast genetic interaction network","volume":"303","author":"AHY Tong","year":"2004","journal-title":"Science"},{"key":"pcbi.1010181.ref030","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.molcel.2012.05.028","article-title":"Hierarchical Modularity and the Evolution of Genetic Interactomes across Species","volume":"46","author":"CJ Ryan","year":"2012","journal-title":"Molecular Cell"},{"key":"pcbi.1010181.ref031","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nmeth.4627","article-title":"Using deep learning to model the hierarchical structure and function of a cell.","volume":"15","author":"J Ma","year":"2018","journal-title":"Nat Methods."},{"key":"pcbi.1010181.ref032","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1756-0381-4-10","article-title":"Using graph theory to analyze biological networks.","volume":"4","author":"GA Pavlopoulos","year":"2011","journal-title":"BioData Min"},{"key":"pcbi.1010181.ref033","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1146\/annurev.genet.40.110405.090613","article-title":"Mitochondrial retrograde signaling","volume":"40","author":"Z Liu","year":"2006","journal-title":"Annual Review of Genetics"},{"key":"pcbi.1010181.ref034","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1002\/j.1460-2075.1995.tb07106.x","article-title":"AFT1: a mediator of iron regulated transcriptional control in Saccharomyces cerevisiae","volume":"14","author":"Y Yamaguchi-Iwai","year":"1995","journal-title":"EMBO J"},{"key":"pcbi.1010181.ref035","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1046\/j.1365-2958.2001.02627.x","article-title":"The role of the yeast plasma membrane SPS nutrient sensor in the metabolic response to extracellular amino acids","volume":"42","author":"H Forsberg","year":"2001","journal-title":"Mol Microbiol"},{"key":"pcbi.1010181.ref036","doi-asserted-by":"crossref","first-page":"a005314","DOI":"10.1101\/cshperspect.a005314","article-title":"Signaling at the Golgi.","volume":"3","author":"P. Mayinger","year":"2011","journal-title":"Cold Spring Harb Perspect Biol."},{"key":"pcbi.1010181.ref037","doi-asserted-by":"crossref","first-page":"246","DOI":"10.5483\/BMBRep.2021.54.5.270","article-title":"The Golgi complex: a hub of the secretory pathway.","volume":"54","author":"K Park","year":"2021","journal-title":"BMB Rep."},{"key":"pcbi.1010181.ref038","doi-asserted-by":"crossref","first-page":"432","DOI":"10.3390\/life11050432","article-title":"Interplay between Mitochondrial Protein Import and Respiratory Complexes Assembly in Neuronal Health and Degeneration.","volume":"11","author":"HI Needs","year":"2021","journal-title":"Life"},{"key":"pcbi.1010181.ref039","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/0092-8674(93)90050-Z","article-title":"RTG1 and RTG2: Two yeast genes required for a novel path of communication from mitochondria to the nucleus","volume":"72","author":"X Liao","year":"1993","journal-title":"Cell"},{"key":"pcbi.1010181.ref040","first-page":"795","article-title":"RTG-dependent Mitochondria-to-Nucleus Signaling Is Regulated by MKS1 and Is Linked to Formation of Yeast Prion [URE3]","volume":"13","author":"T Sekito","year":"2002","journal-title":"Mol Biol Cell"},{"key":"pcbi.1010181.ref041","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1534\/g3.117.040220","article-title":"TheCellMap.org: A Web-Accessible Database for Visualizing and Mining the Global Yeast Genetic Interaction Network.","volume":"7","author":"M Usaj","year":"2017","journal-title":"G3 (Bethesda)."},{"key":"pcbi.1010181.ref042","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1534\/genetics.113.152082","article-title":"Kinetochore Function and Chromosome Segregation Rely on Critical Residues in Histones H3 and H4 in Budding Yeast.","volume":"195","author":"TM Ng","year":"2013","journal-title":"Genetics"},{"key":"pcbi.1010181.ref043","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1128\/MCB.00770-15","article-title":"Reduced Histone Expression or a Defect in Chromatin Assembly Induces Respiration","volume":"36","author":"L Galdieri","year":"2016","journal-title":"Mol Cell Biol"},{"key":"pcbi.1010181.ref044","doi-asserted-by":"crossref","first-page":"e201800278","DOI":"10.26508\/lsa.201800278","article-title":"A network of human functional gene interactions from knockout fitness screens in cancer cells","volume":"2","author":"E Kim","year":"2019","journal-title":"Life Science Alliance"},{"key":"pcbi.1010181.ref045","first-page":"1751","article-title":"Hitting and Commute Times in Large Random Neighborhood Graphs.","volume":"15","author":"U von Luxburg","year":"2014","journal-title":"J Mach Learn Res"},{"key":"pcbi.1010181.ref046","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1021\/ct050307u","article-title":"A New Method for Coarse-Grained Elastic Normal-Mode Analysis.","volume":"2","author":"M Lu","year":"2006","journal-title":"J Chem Theory Comput."},{"key":"pcbi.1010181.ref047","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1002\/spe.4380211102","article-title":"Graph drawing by force-directed placement","volume":"21","author":"TMJ Fruchterman","year":"1991","journal-title":"Softw Pract Exp"},{"key":"pcbi.1010181.ref048","doi-asserted-by":"crossref","unstructured":"Hagberg AA, Schult DA, Swart PJ. Exploring network structure, dynamics, and function using NetworkX. In: Varoquaux G, Vaught T, Millman J, editors. Proceedings of the 7th python in science conference. Pasadena, CA USA; 2008. pp. 11\u201315.","DOI":"10.25080\/TCWV9851"},{"key":"pcbi.1010181.ref049","doi-asserted-by":"crossref","first-page":"W374","DOI":"10.1093\/nar\/gkx385","article-title":"DynOmics: dynamics of structural proteome and beyond","volume":"45","author":"H Li","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010181.ref050","article-title":"ProDy 2.0: Increased Scale and Scope after 10 Years of Protein Dynamics Modelling with Python","author":"S Zhang","year":"2021","journal-title":"Bioinformatics"},{"key":"pcbi.1010181.ref051","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Z Gu","year":"2016","journal-title":"Bioinformatics"},{"key":"pcbi.1010181.ref052","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1086\/341527","article-title":"A Note on the Calculation of Empirical P Values from Monte Carlo Procedures","volume":"71","author":"BV North","year":"2002","journal-title":"Am J Hum Genet"},{"key":"pcbi.1010181.ref053","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-28948-z","article-title":"GOATOOLS: A Python library for Gene Ontology analyses","volume":"8","author":"DV Klopfenstein","year":"2018","journal-title":"Sci Rep"},{"key":"pcbi.1010181.ref054","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/nbt1209-1135","article-title":"How does multiple testing correction work?","volume":"27","author":"WS Noble","year":"2009","journal-title":"Nat Biotechnol"},{"key":"pcbi.1010181.ref055","doi-asserted-by":"crossref","first-page":"99","DOI":"10.2307\/3001913","article-title":"Comparing Individual Means in the Analysis of Variance","volume":"5","author":"JW Tukey","year":"1949","journal-title":"Biometrics"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010181","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010181","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T01:19:15Z","timestamp":1727313555000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010181"}},"subtitle":[],"editor":[{"given":"Jessica C.","family":"Flack","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,5,31]]},"references-count":55,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010181","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.06.04.446730","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,31]]}}}