RNA N6-Methyladenosine (m6A) regulates the cell cycle in Diffuse Midline Glioma (DMG) and confers sensitivity to FTO inhibition

RNA N6-Methyladenosine (m6A) regulates the cell cycle in Diffuse Midline Glioma (DMG) and confers sensitivity to FTO inhibition | 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 RNA N6-Methyladenosine (m6A) regulates the cell cycle in Diffuse Midline Glioma (DMG) and confers sensitivity to FTO inhibition Samuel E. Ross, Holly Holliday, Eyden Wang, Mahdi Zeraati, Maria Tsoli, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5390888/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 Background: Diffuse Midline Gliomas (DMG) are deadly pediatric brain cancers with limited treatment options. These tumors likely arise from oligodendrocyte precursor cells (OPC) that acquire a driver histone mutation, leading to an aberrant epigenome. RNA N6-methyladenosine (m6A) is a vital epi-transcriptomic modification that regulates RNA processes and plays a significant role in OPC development through its regulation of transcripts involved in histone modification processes. Despite this pivotal role in OPC biology, the epi-transcriptome has not yet been investigated in DMG, and its interrogation may uncover new therapeutic options and improve our understanding of this disease. Results: Therefore, for the first time, we generated base-resolution m6A landscapes for patient-derived DMG cultures and revealed a critical role in cell cycle regulation. We also found that DMG is sensitive to the inhibition of the m6A demethylase Fat Mass and Obesity Associated (FTO), with this inhibition leading to decreased survival and S-phase arrest/stress. Additionally, key cell cycle regulators, such as PLK1, are m6A-modified, contain YTHDF2 binding sites, and show significant changes following FTO inhibition on transcriptomic and proteomic levels. Conclusions: Here, we provide the first epi-transcriptomic and m6A resource for DMG and reveal a crucial link between m6A modifications and cell cycle regulation. Furthermore, we show that this relationship confers sensitivity to the inhibition of the m6A demethylase FTO, with inhibition resulting in decreased survival and cell-cycle dysregulation. Collectively, these findings highlight the epi-transcriptome and its regulators as promising therapeutic targets for this currently uncurable disease. RNA methylation N6-Methyladenosine DMG Cancer Epigenetics Full Text Additional Declarations No competing interests reported. Supplementary Files RossetalSupFigures.pdf SupplementalTables.xlsx 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. 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-5390888","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":376626044,"identity":"477afd6d-3131-47ca-a2e2-8bb4b65016ea","order_by":0,"name":"Samuel E. 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These tumors likely arise from oligodendrocyte precursor cells (OPC) that acquire a driver histone mutation, leading to an aberrant epigenome. RNA N6-methyladenosine (m6A) is a vital epi-transcriptomic modification that regulates RNA processes and plays a significant role in OPC development through its regulation of transcripts involved in histone modification processes. Despite this pivotal role in OPC biology, the epi-transcriptome has not yet been investigated in DMG, and its interrogation may uncover new therapeutic options and improve our understanding of this disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eTherefore, for the first time, we generated base-resolution m6A landscapes for patient-derived DMG cultures and revealed a critical role in cell cycle regulation. We also found that DMG is sensitive to the inhibition of the m6A demethylase Fat Mass and Obesity Associated (FTO), with this inhibition leading to decreased survival and S-phase arrest/stress. Additionally, key cell cycle regulators, such as PLK1, are m6A-modified, contain YTHDF2 binding sites, and show significant changes following FTO inhibition on transcriptomic and proteomic levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Here, we provide the first epi-transcriptomic and m6A resource for DMG and reveal a crucial link between m6A modifications and cell cycle regulation. Furthermore, we show that this relationship confers sensitivity to the inhibition of the m6A demethylase FTO, with inhibition resulting in decreased survival and cell-cycle dysregulation. Collectively, these findings highlight the epi-transcriptome and its regulators as promising therapeutic targets for this currently uncurable disease.\u003c/p\u003e","manuscriptTitle":"RNA N6-Methyladenosine (m6A) regulates the cell cycle in Diffuse Midline Glioma (DMG) and confers sensitivity to FTO inhibition","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-18 06:16:43","doi":"10.21203/rs.3.rs-5390888/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7d708800-11ea-45ec-b199-573b1746a486","owner":[],"postedDate":"November 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-12-03T11:08:17+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-18 06:16:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5390888","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5390888","identity":"rs-5390888","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}