An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer

An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer | 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 Research Article An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer Carolina Dibenedetto, Amelia Tsark, Daniza Acenas, Alysia Thach, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9460487/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Highly accessible genomic super-enhancers often drive tumor-promoting programs, yet the impact of genomic variation within these regulatory elements remains unclear. Here, we identified a bifunctional super-enhancer that regulates the expression of cancer-promoting genes LINC00636 and CD47 in breast cancer. We discovered that a common germline insertion variant within the super-enhancer is associated with reduced chromatin accessibility at the super-enhancer locus. Deletion of the insertion in breast cancer cells increased chromatin accessibility, leading to upregulation of LINC00636 and CD47, enhanced resistance to nutrient-deprivation–induced apoptosis (mediated by CD47), activation of senescence (driven by elevated LINC00636), delayed cell death, and reduced infiltration of CD80⁺ pro-inflammatory macrophages, changes that represent tumor-promoting features. Together, our findings uncover a common insertion-deletion variant that fine-tunes the regulatory activity of a bifunctional super-enhancer, suggest a protective role for the insertion allele, and establish a previously unrecognized role for LINC00636 in senescence and breast cancer biology. Super-enhancer genomic variation LINC00636 CD47 breast cancer Full Text Supplementary Files TableS2DEGsInsertiondeletedMCF7.xlsx TableS3DEGsLINC00636overexpression.xlsx TableS4RoleofDEGsincancer.xlsx DocumentS1.pdf Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 04 May, 2026 Editor assigned by journal 24 Apr, 2026 First submitted to journal 22 Apr, 2026 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-9460487","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":634056701,"identity":"120c1ee5-5d86-4781-972c-5b64b1f063b0","order_by":0,"name":"Carolina Dibenedetto","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"","lastName":"Dibenedetto","suffix":""},{"id":634056702,"identity":"65a58bd9-098d-4fb4-865f-cb011b9cbdcc","order_by":1,"name":"Amelia Tsark","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Amelia","middleName":"","lastName":"Tsark","suffix":""},{"id":634056703,"identity":"488d3105-84f2-4f00-a0c8-b7bb7f87e958","order_by":2,"name":"Daniza Acenas","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Daniza","middleName":"","lastName":"Acenas","suffix":""},{"id":634056704,"identity":"3f45d716-1357-4aae-beb9-e5aa1cc9506c","order_by":3,"name":"Alysia Thach","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Alysia","middleName":"","lastName":"Thach","suffix":""},{"id":634056705,"identity":"d92a443c-5aca-402b-91ba-d5f6827e7cd9","order_by":4,"name":"Anmol Singhal","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Anmol","middleName":"","lastName":"Singhal","suffix":""},{"id":634056706,"identity":"646bad8d-2ea3-4750-960b-eb2bc6981f64","order_by":5,"name":"Valentina Opazo-Mellado","email":"","orcid":"","institution":"Fundación Ciencia y Vida: Fundacion Ciencia \u0026 Vida","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Opazo-Mellado","suffix":""},{"id":634056707,"identity":"11151024-5580-4fb0-a7f5-a2f3042bfe3c","order_by":6,"name":"Anthony Rodriguez Lemus","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"Rodriguez","lastName":"Lemus","suffix":""},{"id":634056708,"identity":"3115e3c8-d0f6-465a-be22-d58749ba25cf","order_by":7,"name":"Mustapha El Zeini","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Mustapha","middleName":"El","lastName":"Zeini","suffix":""},{"id":634056709,"identity":"0a2f654a-80d4-4149-9104-70f4170e4b83","order_by":8,"name":"Hui Zhang","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Zhang","suffix":""},{"id":634056710,"identity":"ccc960a1-255c-4f73-ba7a-0d0178829d24","order_by":9,"name":"Catherine Park","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Catherine","middleName":"","lastName":"Park","suffix":""},{"id":634056711,"identity":"4049ba52-319b-4d72-bc1c-0c26c37bf5e3","order_by":10,"name":"Hugo Gonzalez Velozo","email":"","orcid":"","institution":"University of California San Francisco","correspondingAuthor":false,"prefix":"","firstName":"Hugo","middleName":"Gonzalez","lastName":"Velozo","suffix":""},{"id":634056712,"identity":"a4d33736-f6ed-4897-b603-1b71db6548b3","order_by":11,"name":"Irving Weissmann","email":"","orcid":"","institution":"Stanford University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Irving","middleName":"","lastName":"Weissmann","suffix":""},{"id":634056713,"identity":"b4aaa197-fafa-4dec-a568-a76f0f26dc49","order_by":12,"name":"Paola Betancur","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYHACxgMMDAdgHBuQwAMGBjb8esBaeCDsNCBmNiBJy2HCWszZDx848IPhjpw9+9mDn3n3nE/s7wdq+1B2GKcWy560hIM9DM+MeXjykqV5nt1OnHEjmYFxxjncWgwO5Bgc4GE4nNjDkGPGzHPgduIGCf4DzLxteLScf2Nw8A/D4foe/jcgLecSN/AfZmD+i0/LjRyDw0BbEngkwLYcSNzAkMzAzIhHi+WMZwmHZQyeGfbceGMsOedAsjHILwd7zqXj1GLOn3zw4ZuKO/Ls/TmGH94csJMFhhjjgx9l1rgdhkQiwAGc6rEoHgWjYBSMglGACQCKUlpVdmOeuwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-9011-4746","institution":"University of California San Francisco","correspondingAuthor":true,"prefix":"","firstName":"Paola","middleName":"","lastName":"Betancur","suffix":""}],"badges":[],"createdAt":"2026-04-19 08:26:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9460487/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9460487/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109123633,"identity":"6aa5ccd3-38c0-4494-9558-4c0c12013c5d","added_by":"auto","created_at":"2026-05-12 18:02:44","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1172787,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptfinalCellularandMolecularLifeSciencesPB.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9460487/v1_covered_6e6a32c4-0865-41f9-aa6a-fb7cf84c5d1d.pdf"},{"id":109123625,"identity":"ffb0853f-b12e-4ede-8eb3-1d0516d5dd9a","added_by":"auto","created_at":"2026-05-12 18:02:30","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":402340,"visible":true,"origin":"","legend":"","description":"","filename":"TableS2DEGsInsertiondeletedMCF7.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-9460487/v1/fe67665f851b058c30336a7b.xlsx"},{"id":109123626,"identity":"9e2d41df-3b34-4c3d-81a9-ee0fed6f33a0","added_by":"auto","created_at":"2026-05-12 18:02:30","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":202608,"visible":true,"origin":"","legend":"","description":"","filename":"TableS3DEGsLINC00636overexpression.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-9460487/v1/426f7eeda567e8cd3eec51c4.xlsx"},{"id":109123624,"identity":"416a4050-1c62-4c6f-8650-0b5b240880a2","added_by":"auto","created_at":"2026-05-12 18:02:30","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":19078,"visible":true,"origin":"","legend":"","description":"","filename":"TableS4RoleofDEGsincancer.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-9460487/v1/f1dd657862deeff59592e2a0.xlsx"},{"id":109123623,"identity":"13a65c8f-5a2b-4966-8be0-ae3919b6b5d5","added_by":"auto","created_at":"2026-05-12 18:02:30","extension":"pdf","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":744233,"visible":true,"origin":"","legend":"","description":"","filename":"DocumentS1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9460487/v1/7f1c7cf1327159f8c50daae9.pdf"}],"financialInterests":"","formattedTitle":"An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer","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":"cellular-and-molecular-life-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"life","sideBox":"Learn more about [Cellular and Molecular Life Sciences](https://link.springer.com/journal/18)","snPcode":"18","submissionUrl":"https://www.editorialmanager.com/life/default2.aspx","title":"Cellular and Molecular Life Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Super-enhancer, genomic variation, LINC00636, CD47, breast cancer","lastPublishedDoi":"10.21203/rs.3.rs-9460487/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9460487/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHighly accessible genomic super-enhancers often drive tumor-promoting programs, yet the impact of genomic variation within these regulatory elements remains unclear. Here, we identified a bifunctional super-enhancer that regulates the expression of cancer-promoting genes LINC00636 and CD47 in breast cancer. We discovered that a common germline insertion variant within the super-enhancer is associated with reduced chromatin accessibility at the super-enhancer locus. Deletion of the insertion in breast cancer cells increased chromatin accessibility, leading to upregulation of LINC00636 and CD47, enhanced resistance to nutrient-deprivation–induced apoptosis (mediated by CD47), activation of senescence (driven by elevated LINC00636), delayed cell death, and reduced infiltration of CD80⁺ pro-inflammatory macrophages, changes that represent tumor-promoting features. Together, our findings uncover a common insertion-deletion variant that fine-tunes the regulatory activity of a bifunctional super-enhancer, suggest a protective role for the insertion allele, and establish a previously unrecognized role for LINC00636 in senescence and breast cancer biology.\u003c/p\u003e","manuscriptTitle":"An InDel Genomic Variant within a Bifunctional Super-Enhancer for LINC00636 and CD47 Regulation in Breast Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-12 18:02:26","doi":"10.21203/rs.3.rs-9460487/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-05-04T10:29:49+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-24T13:17:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cellular and Molecular Life Sciences","date":"2026-04-22T18:30:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cellular-and-molecular-life-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"life","sideBox":"Learn more about [Cellular and Molecular Life Sciences](https://link.springer.com/journal/18)","snPcode":"18","submissionUrl":"https://www.editorialmanager.com/life/default2.aspx","title":"Cellular and Molecular Life Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Open","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d399d481-2ec2-4dd8-9cab-24f59dea5144","owner":[],"postedDate":"May 12th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewersInvited","content":"","date":"2026-05-04T10:29:49+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-12T18:02:26+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-12 18:02:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9460487","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9460487","identity":"rs-9460487","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}