Plasticity of X-chromosome inactivation in female reproduction

Plasticity of X-chromosome inactivation in female reproduction | 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 Plasticity of X-chromosome inactivation in female reproduction Alejandro Caceres, Albert Alegret-García, Alicia Barberan, Mariona Bustamante, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8764864/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 X-chromosome inactivation (XCI) is a mammalian mechanism for dosage compensation, yet its dynamics across reproductive states remain poorly characterized. Here we identify XCI plasticity in female reproductive tissues, including the endometrium and maternal immune cells. Single-cell transcriptomic analyses show that proliferating endometrial stromal cells exhibit the highest silenced-to-escape expression ratio (STER)—a relative measure of expression balance between XCI-silenced and canonical escape X-linked genes—accompanied by reduced allelic imbalance of silenced genes, before sharply declining during decidualization. In contrast, maternal immune cells maintain a low STER with increased XIST expression across gestation. Epigenetic profiling reveals increased biallelic demethylation of silenced genes during endometrial proliferation. This biallelic demethylation is reduced in maternal blood during healthy gestation but increased in complicated pregnancies and in nulliparous women. Cross-species analyses reveal similar XCI plasticity in subfertile cattle and strong correlations between baseline XCI dynamics and lifetime reproductive potential across mammals. Together, these findings establish XCI plasticity as a dynamic feature of mammalian reproduction. Biological sciences/Genetics/Epigenetics Health sciences/Medical research/Genetics research Full Text Additional Declarations Yes there is potential Competing Interest. LPJ is a member of the scientific board of qGenomics. BVD and RS are employed by TruDiagnostics. All other authors declare that they have no competing interests. Supplementary Files SupplementaryFigures.docx Suppemantal material TableS1.xlsx Table S1 TableS2.xlsx Table S2 TableS3.xlsx Table S3 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-8764864","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":601335341,"identity":"036c1db4-228f-4d2a-8848-cf389ddebfee","order_by":0,"name":"Alejandro 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All other authors declare that they have no competing interests.","formattedTitle":"Plasticity of X-chromosome inactivation in female reproduction","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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-8764864/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8764864/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"X-chromosome inactivation (XCI) is a mammalian mechanism for dosage compensation, yet its dynamics across reproductive states remain poorly characterized. Here we identify XCI plasticity in female reproductive tissues, including the endometrium and maternal immune cells. Single-cell transcriptomic analyses show that proliferating endometrial stromal cells exhibit the highest silenced-to-escape expression ratio (STER)—a relative measure of expression balance between XCI-silenced and canonical escape X-linked genes—accompanied by reduced allelic imbalance of silenced genes, before sharply declining during decidualization. In contrast, maternal immune cells maintain a low STER with increased XIST expression across gestation. Epigenetic profiling reveals increased biallelic demethylation of silenced genes during endometrial proliferation. This biallelic demethylation is reduced in maternal blood during healthy gestation but increased in complicated pregnancies and in nulliparous women. Cross-species analyses reveal similar XCI plasticity in subfertile cattle and strong correlations between baseline XCI dynamics and lifetime reproductive potential across mammals. 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