Operating principles of coupled feedback networks driving cell fate transitions

Operating principles of coupled feedback networks driving cell fate transitions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Operating principles of coupled feedback networks driving cell fate transitions Mubasher Rashid, abhiram Hegade This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4776266/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Jan, 2025 Read the published version in npj Systems Biology and Applications → Version 1 posted 9 You are reading this latest preprint version Abstract Interconnected feedback loops are prevalent across biological mechanisms including cell fate transitions enabled by epigenetic mechanisms driving phenotypic plasticity of carcinoma cells. However, the operating principles of these networks remain largely unexplored. Here, we identify numerous coupled feedback loops driving phenotypic transition in carcinomas and CD4+ T cell lineage decisions. These networks have three generic structures, serial type (ST), hub type (HT), and cyclic, which we discover to be the hallmarks of lower- and higher-order dynamics. While networks having ST or cyclic topology exhibit multiple alternative states, those having HT topology enable at most two states. Irrespective of the topology, networks with autoregulated genes exhibit multiple states thereby “liberating” network dynamics from absolute topological control. We further show that topologically distinct networks with equal node or loop count exhibit different steady-state distributions, highlighting the crucial influence of network structure on emergent dynamics. Finally, we identify precise gene interaction targets to restrict the multistable network dynamics to a unique state. Our results thus unravel design principles of coupled feedback loops in enabling multiple alternative states while also identifying perturbations to restrict them. These findings can serve as crucial inputs to comprehend multi-fate decisions of cells and phenotypic plasticity in carcinomas. Biological sciences/Systems biology/Regulatory networks Biological sciences/Systems biology/Multistability Cell fate transition Gene regulatory networks Coupled feedback loops Multistability Topology-dynamics association Full Text Additional Declarations (Not answered) Competing interests: The authors declare no competing interests. Supplementary Files SupplementaryMaterialJuly212024.pdf Cite Share Download PDF Status: Published Journal Publication published 02 Jan, 2025 Read the published version in npj Systems Biology and Applications → Version 1 posted Editorial decision: revise 23 Aug, 2024 Review # 2 received at journal 22 Aug, 2024 Review # 1 received at journal 08 Aug, 2024 Reviewer # 2 agreed at journal 06 Aug, 2024 Reviewer # 1 agreed at journal 04 Aug, 2024 Reviewers invited by journal 31 Jul, 2024 Editor assigned by journal 23 Jul, 2024 Submission checks completed at journal 23 Jul, 2024 First submitted to journal 21 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4776266","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":334236136,"identity":"ae8390f4-38f6-4895-99aa-b72e0331bb92","order_by":0,"name":"Mubasher Rashid","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9klEQVRIiWNgGAWjYFACHgYGxgYwi40hgc0GSDM2HiBFSxpISwMJWhjYDoNZeLXozsg9+PHnDpt88/bjzx48KDtvt7b9MNCWGptoXFrMbuQlS/OeSbOccybH3CDh3O3kbWcSgVqOpeU24NSSYyDN2HbYQIIhh00ise12stkBoBbGhsP4tBj//Nn230CC//kzoJZzyWbnHxLUYibB23bAQEIiwQyo5YCd2Q1Ctpx5l2bN25YM1PLGTCLhXHKC2Q2gLQn4/HI89/DNn212QIelP5P8UWZnb3Y+/eGDDzU2OLVggESwygRilYOAPSmKR8EoGAWjYGQAAJCEZLPYSH4CAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-2790-6147","institution":"IIT Kanpur","correspondingAuthor":true,"prefix":"","firstName":"Mubasher","middleName":"","lastName":"Rashid","suffix":""},{"id":334236137,"identity":"897b1ab9-7f7d-4d47-9c22-97c688579754","order_by":1,"name":"abhiram Hegade","email":"","orcid":"","institution":"University of Florida, Gainesville","correspondingAuthor":false,"prefix":"","firstName":"abhiram","middleName":"","lastName":"Hegade","suffix":""}],"badges":[],"createdAt":"2024-07-21 10:05:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4776266/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4776266/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41540-024-00483-w","type":"published","date":"2025-01-02T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":73059115,"identity":"b137f3f2-211f-4957-a4f5-673aaba4de27","added_by":"auto","created_at":"2025-01-06 10:45:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1969689,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptJuly212024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4776266/v1_covered_e7f49049-b831-4f34-8a13-d68e966daf05.pdf"},{"id":63047068,"identity":"df4de302-9779-45bd-a81c-d7837605fbc6","added_by":"auto","created_at":"2024-08-22 13:03:37","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2354631,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"SupplementaryMaterialJuly212024.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4776266/v1/b1e98b85a7474c576bbea529.pdf"}],"financialInterests":"\u003cp\u003e(Not answered)\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare no competing interests.\u003c/p\u003e","formattedTitle":"Operating principles of coupled feedback networks driving cell fate transitions","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-systems-biology-and-applications","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"npjsba","sideBox":"Learn more about [npj Systems Biology and Applications](http://www.nature.com/npjsba/)","snPcode":"41540","submissionUrl":"https://submission.springernature.com/new-submission/41540/3","title":"npj Systems Biology and Applications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cell fate transition, Gene regulatory networks, Coupled feedback loops, Multistability, Topology-dynamics association","lastPublishedDoi":"10.21203/rs.3.rs-4776266/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4776266/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Interconnected feedback loops are prevalent across biological mechanisms including cell fate transitions enabled by epigenetic mechanisms driving phenotypic plasticity of carcinoma cells. 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