BRD2 impedes iPSC reprogramming by regulating lipogenesis and matrisome

BRD2 impedes iPSC reprogramming by regulating lipogenesis and matrisome | 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 BRD2 impedes iPSC reprogramming by regulating lipogenesis and matrisome Kejin Hu, Ricardo Cevallos, Ruowen Zhang, Shu Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7744310/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Induction of human pluripotent stem cells (HiPSCs) from somatic cells encounters significant barriers, which remain poorly understood. Lipids are fundamental cellular molecules with many essential roles. However, lipid roles in reprogramming are unknown. Here, we prove that BRD2 is a barrier to HiPSC reprogramming by suppressing lipogenesis and maintaining the somatic transcriptional program, particularly the somatic matrisome program. Strikingly, the acetylation epigenetic reader BRD2 unorthodoxically suppressed gene expression of lipogenesis in the reprogramming cells. The two rate-limiting enzymes of lipogenesis, SCD and HMGCR, enhanced iPSC reprogramming while lipid supplements enhanced it. Interestingly, the BRD2 ET tail suppressed reprogramming and the lipogenesis transcriptional program but positively regulated matrisome program. In line with its transcriptional suppression of lipogenesis, BRD2 binds to genes of lipogenesis and negatively regulates their H3K27Ac status. These discoveries advance our knowledge of HiPSC reprogramming by revealing the opposite BRD2 regulatory roles on matrisome and lipogenesis in promoting reprogramming. Biological sciences/Stem cells/Reprogramming Biological sciences/Molecular biology/Transcriptomics Biological sciences/Genetics/Genomics/Transcriptomics Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Under Review 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7744310","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":525626038,"identity":"ca8ff439-5d23-42a9-ad28-44064815c42b","order_by":0,"name":"Kejin Hu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIie3OsQqCQBzH8V8EtZy43hHZKxjt9Sont1o4NgqCLkKr0UsIQvPBDS0+gENDETS1tTp04tKkjkH33e74f/j/AZPpB6MAl4CErR/j9o8PJCzEKBpKmiRcOZSwJLyrAFevqLaXR1CvYU99t5PMiOQqw9M7VzsvOsYCLH11E4dyrgiUJv4yskJ9YdWzxVncWlJkmpBaYtNHZhQtyWlDJnoL7SEsbQ5z1SorX8uTFQtCy2fQSeilFG+yV/ND4rtvUq8dOxF5JwEIB74uIT3jTVM5YMhkMpn+ug8qwUpB9NsdiAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-3111-4054","institution":"UNT Health Science Center","correspondingAuthor":true,"prefix":"","firstName":"Kejin","middleName":"","lastName":"Hu","suffix":""},{"id":525626039,"identity":"378305bb-5dc0-40be-a3a7-1670db7f43e5","order_by":1,"name":"Ricardo Cevallos","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Ricardo","middleName":"","lastName":"Cevallos","suffix":""},{"id":525626040,"identity":"ef8e60cb-7658-4071-81c9-c4238c2c8a10","order_by":2,"name":"Ruowen Zhang","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Ruowen","middleName":"","lastName":"Zhang","suffix":""},{"id":525626041,"identity":"131a15e9-3674-4a5a-b11a-e7f0239f361e","order_by":3,"name":"Shu Chen","email":"","orcid":"","institution":"University of Alabama at Birmingham","correspondingAuthor":false,"prefix":"","firstName":"Shu","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2025-09-29 17:20:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7744310/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7744310/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97670594,"identity":"7dcdf53d-9ac8-4f2f-ab04-2f7ad14a9c18","added_by":"auto","created_at":"2025-12-08 09:31:00","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2719104,"visible":true,"origin":"","legend":"Article File","description":"","filename":"BRD2iPSCHu.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7744310/v1_covered_9885abcd-8cc2-466e-9d56-f2669a43a6ff.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"BRD2 impedes iPSC reprogramming by regulating lipogenesis and matrisome","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7744310/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7744310/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Induction of human pluripotent stem cells (HiPSCs) from somatic cells encounters significant barriers, which remain poorly understood. Lipids are fundamental cellular molecules with many essential roles. However, lipid roles in reprogramming are unknown. Here, we prove that BRD2 is a barrier to HiPSC reprogramming by suppressing lipogenesis and maintaining the somatic transcriptional program, particularly the somatic matrisome program. Strikingly, the acetylation epigenetic reader BRD2 unorthodoxically suppressed gene expression of lipogenesis in the reprogramming cells. The two rate-limiting enzymes of lipogenesis, SCD and HMGCR, enhanced iPSC reprogramming while lipid supplements enhanced it. Interestingly, the BRD2 ET tail suppressed reprogramming and the lipogenesis transcriptional program but positively regulated matrisome program. In line with its transcriptional suppression of lipogenesis, BRD2 binds to genes of lipogenesis and negatively regulates their H3K27Ac status. These discoveries advance our knowledge of HiPSC reprogramming by revealing the opposite BRD2 regulatory roles on matrisome and lipogenesis in promoting reprogramming.","manuscriptTitle":"BRD2 impedes iPSC reprogramming by regulating lipogenesis and matrisome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-05 04:37:34","doi":"10.21203/rs.3.rs-7744310/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-biology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsbio","sideBox":"Learn more about [Communications Biology](http://www.nature.com/commsbio/)","snPcode":"","submissionUrl":"","title":"Communications Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"affea4f7-4d50-40f2-afcc-f1943788a085","owner":[],"postedDate":"December 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":55862539,"name":"Biological sciences/Stem cells/Reprogramming"},{"id":55862540,"name":"Biological sciences/Molecular biology/Transcriptomics"},{"id":55862541,"name":"Biological sciences/Genetics/Genomics/Transcriptomics"}],"tags":[],"updatedAt":"2025-12-05T04:37:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-05 04:37:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7744310","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7744310","identity":"rs-7744310","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}