The transcriptional repressor AEBP2 is indispensable for the epigenetic control of mimetic thymic epithelial cell differentiation and central self-tolerance induction

The transcriptional repressor AEBP2 is indispensable for the epigenetic control of mimetic thymic epithelial cell differentiation and central self-tolerance induction | 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 The transcriptional repressor AEBP2 is indispensable for the epigenetic control of mimetic thymic epithelial cell differentiation and central self-tolerance induction Wei Wu, Kevin Rue-Albrecht, Qian Cheng, Fatima Dhalla, Mary Deadman, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7382433/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The polycomb repressive complex 2 (PRC2) catalyses the addition of H3K27me3 marks to chromatin and thus modifies gene repression controlling the differentiation and function of medullary TECs (mTECs). The zinc finger protein AEBP2 physically interacts with PRC2 as a non-essential core component of the complex, yet its precise role in TEC biology remains untested. Here, we demonstrate that a TEC-targeted loss of AEBP2 expression in mice increases TEC and total thymic cellularity yet unexpectedly impairs the differentiation and maintenance of mimetic TEC subtypes. AEBP2-deficient mTECs display H3K27me3-dependent modifications in chromatin accessibility which compromises the capacity to promiscuously express tissue-restricted genes (TRGs). Consequently, severe lymphocytic infiltrates are observed in peripheral tissues as a result of flawed central T cell tolerance induction. Taken together, these findings highlight the essential, context-dependent role of AEBP2 in TEC differentiation and function via its impact on chromatin structure, transcriptional regulation, and developmental programming. Biological sciences/Immunology/Autoimmunity Biological sciences/Cell biology Full Text Additional Declarations There is NO Competing Interest. Aebp2 constitutive knockout mice were maintained under specific pathogen-free conditions at the John Radcliffe Hospital Mouse Facility, University of Oxford. Aebp2 conditional knockout mice were maintained under specific pathogen-free conditions at the Shanghai Model Organisms Center. Foxn1-Cre mice were obtained from the Shanghai Model Organisms Center. All animal procedures were performed in accordance with institutional guidelines and were approved by the respective Animal Ethics Committees. Cite Share Download PDF Status: Posted Version 1 posted 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. 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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-7382433","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":509247891,"identity":"93f4fee9-e9bc-4863-b890-dbe83db4caeb","order_by":0,"name":"Wei Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYBADHjb25oMPEipqiNciw8dzLNngwZljxGuxkZPIMZN82MJMWKnB8TNmDz62HeZhY0gwq0hsYGPgb+9OwK/lTI654UywlgNpNxJ3yDBInDm7Aa8WswM5ZtK824BaGBuO3Ug8w8ZgIJFLQMv5N2bSf0FamBnbChLbmInQcgNoCyNICxszGwNRWuxvPCuT7P2XzsMGtEci4cwxHoJ+kexP3ibx44y1vfz89x8//qiokeNv78WvhYGBwwCFy0NAOQiwPyBC0SgYBaNgFIxoAABWlEevD/tQCgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-8268-6525","institution":"Zhongshan Hospital, Fudan University","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Wu","suffix":""},{"id":509247892,"identity":"49140ce8-fbf0-435f-9957-4abe80702de3","order_by":1,"name":"Kevin Rue-Albrecht","email":"","orcid":"https://orcid.org/0000-0003-3899-3872","institution":"University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Kevin","middleName":"","lastName":"Rue-Albrecht","suffix":""},{"id":509247893,"identity":"de5f97c9-2e29-4240-a315-dc13c8f77e41","order_by":2,"name":"Qian Cheng","email":"","orcid":"","institution":"University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Qian","middleName":"","lastName":"Cheng","suffix":""},{"id":509247894,"identity":"77ae8a8d-51f9-48cb-b878-04d5b9092636","order_by":3,"name":"Fatima Dhalla","email":"","orcid":"","institution":"Department of Paediatrics, University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Fatima","middleName":"","lastName":"Dhalla","suffix":""},{"id":509247895,"identity":"5a571b5d-4bab-4e6b-a22f-9aebef9e692b","order_by":4,"name":"Mary Deadman","email":"","orcid":"","institution":"University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Mary","middleName":"","lastName":"Deadman","suffix":""},{"id":509247896,"identity":"7b059273-fc84-4759-a19a-254f53a1dddd","order_by":5,"name":"Rongyu Zang","email":"","orcid":"","institution":"Department of Gynaecologic Oncology, Zhongshan Hospital, Fudan University","correspondingAuthor":false,"prefix":"","firstName":"Rongyu","middleName":"","lastName":"Zang","suffix":""},{"id":509247897,"identity":"21ec4545-6d85-404a-9f6b-1e67354ed20e","order_by":6,"name":"Stephen Sansom","email":"","orcid":"https://orcid.org/0000-0003-4569-8513","institution":"University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Stephen","middleName":"","lastName":"Sansom","suffix":""},{"id":509247898,"identity":"f0d9b547-8155-4786-8d6f-45254aaeced2","order_by":7,"name":"Yiyan Zheng","email":"","orcid":"","institution":"Westlake Laboratory of Life Sciences and Biomedicine","correspondingAuthor":false,"prefix":"","firstName":"Yiyan","middleName":"","lastName":"Zheng","suffix":""},{"id":509247899,"identity":"c6e4652f-a948-4c3e-8e8e-7559fb432347","order_by":8,"name":"Georg Hollander","email":"","orcid":"https://orcid.org/0000-0002-8790-0874","institution":"University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Georg","middleName":"","lastName":"Hollander","suffix":""}],"badges":[],"createdAt":"2025-08-15 15:10:41","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7382433/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7382433/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":92122807,"identity":"eecceb72-1104-41e2-9f40-7fec24f02c1b","added_by":"auto","created_at":"2025-09-24 23:03:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5155277,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Aebp2inTECMS.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7382433/v1_covered_b9c997c2-035c-47d6-849a-80d82aa772d8.pdf"}],"financialInterests":"\u003cp\u003eThere is \u003cstrong\u003eNO\u003c/strong\u003e Competing Interest.\u003c/p\u003e\n\u003cp\u003eAebp2 constitutive knockout mice were maintained under specific pathogen-free conditions at the John Radcliffe Hospital Mouse Facility, University of Oxford. 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