{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T06:10:51Z","timestamp":1788329451258,"version":"build-2803163510"},"reference-count":92,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"General Research Fund","award":["17112422"],"award-info":[{"award-number":["17112422"]}]},{"DOI":"10.13039\/501100001809","name":"NSFC","doi-asserted-by":"publisher","award":["CRS_HKU703\/22"],"award-info":[{"award-number":["CRS_HKU703\/22"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>N 6-methyladenosine (m6A) is the most prevalent messenger RNA modification with diverse regulatory roles in mammalian cells. While its functions are well-documented in mouse embryonic stem cells (mESCs), its role in human pluripotent stem cells (hPSCs) remains to be fully explored. METTL3 is the main enzyme responsible for m6A deposition. Here, using a METTL3 inducible knockout (iKO) system, we uncovered that, unlike in mESCs, METTL3 was indispensable for hPSC maintenance. Importantly, loss of METTL3 caused significant upregulation of pluripotency factors including na\u00efve pluripotency genes and failure to exit pluripotency, thus impairing stem cell differentiation towards both embryonic and extraembryonic cell lineages. Mechanistically, METTL3 iKO in hPSCs promoted expression and enhancer activities of two primate-specific transposable elements (TEs), SVA_D and HERVK\/LTR5_Hs. At SVA_D elements, loss of METTL3 leads to reduced H3K9me3 deposition. On the other hand, the activation of LTR5_Hs in the METTL3 iKO cells is accompanied by increased chromatin accessibility and binding pluripotency factors. The activated SVA_D and LTR5_Hs elements can act as enhancers and promote nearby na\u00efve gene expression by directly interacting with their promoters. Together these findings reveal that METTL3-dependent m6A RNA methylation plays critical roles in suppressing TE expression and in regulating the human pluripotency\u00a0network.<\/jats:p>","DOI":"10.1093\/nar\/gkaf349","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T10:01:41Z","timestamp":1745920901000},"source":"Crossref","is-referenced-by-count":11,"title":["METTL3-dependent m6A RNA methylation regulates transposable elements and represses human na\u00efve pluripotency through transposable element-derived enhancers"],"prefix":"10.1093","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9530-8088","authenticated-orcid":false,"given":"Weiyu","family":"Zhang","sequence":"first","affiliation":[{"name":"Centre for Translational Stem Cell Biology, The University of Hong Kong , Hong Kong Special Administrative Region ,\u00a0","place":["China"]},{"name":"Cornell University Department of Molecular Biology and Genetics, , Ithaca , NY \u00a014853,\u00a0","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1174-9220","authenticated-orcid":false,"given":"Haifeng","family":"Fu","sequence":"additional","affiliation":[{"name":"Stem Cell & Regenerative Medicine Consortium, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong Special Administrative Region,\u00a0","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunying","family":"Huang","sequence":"additional","affiliation":[{"name":"Stem Cell & Regenerative Medicine Consortium, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong Special Administrative Region,\u00a0","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Zeng","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University Department of Obstetrics and Gynecology, , Guangzhou\u00a0 510150 ,","place":["China"]},{"name":"Key laboratory for reproductive Medicine of Guangdong Province, The Third affiliated Hospital of Guangzhou Medical University , Guangzhou\u00a0 510150 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Stem Cell & Regenerative Medicine Consortium, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong Special Administrative 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Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong Special Administrative Region,\u00a0","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinning","family":"Hu","sequence":"additional","affiliation":[{"name":"Centre for Translational Stem Cell Biology, The University of Hong Kong , Hong Kong Special Administrative Region ,\u00a0","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jilong","family":"Guo","sequence":"additional","affiliation":[{"name":"Stem Cell & Regenerative Medicine Consortium, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong , Hong Kong Special Administrative Region,\u00a0","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin W","family":"Galardi","sequence":"additional","affiliation":[{"name":"Cornell University Department of Molecular Biology and Genetics, , Ithaca , NY \u00a014853,\u00a0","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon","family":"Dougan","sequence":"additional","affiliation":[{"name":"Centre for Translational Stem Cell Biology, The University of Hong Kong , Hong Kong Special Administrative Region ,\u00a0","place":["China"]},{"name":"Jeffrey Cheah Biomedical Centre, Cambridge University, Puddicombe Way, Cambridge Biomedical Campus Department of Medicine, , Cambridge CB2 0AW ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William S B","family":"Yeung","sequence":"additional","affiliation":[{"name":"Centre for Translational Stem Cell Biology, The University of Hong Kong , Hong Kong Special Administrative Region ,\u00a0","place":["China"]},{"name":"School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong Department of Obstetrics and Gynaecology, , Hong Kong Special Administrative Region,","place":["China"]},{"name":"Shenzhen Key Laboratory of Fertility Regulation, Reproductive Medicine Center, The University of Hong Kong - Shenzhen Hospital , Shenzhen\u00a0 518000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7544-2191","authenticated-orcid":false,"given":"Lei","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University Department of Obstetrics and Gynecology, , Guangzhou\u00a0 510150 ,","place":["China"]},{"name":"Key laboratory for reproductive Medicine of Guangdong Province, The Third affiliated Hospital of Guangzhou Medical University , Guangzhou\u00a0 510150 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4061-3333","authenticated-orcid":false,"given":"Jianqiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine, The Third Affiliated Hospital of Guangzhou Medical University Department of Obstetrics and Gynecology, , Guangzhou\u00a0 510150 ,","place":["China"]},{"name":"Key laboratory for reproductive Medicine of Guangdong Province, The Third affiliated Hospital of Guangzhou Medical University , Guangzhou\u00a0 510150 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