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However, the roles of E proteins in the germ-layer specification of human embryonic stem cells (hESC) are poorly understood. We disrupted the TCF3 gene locus to delete the E protein E2A in hESCs. E2A KO hESCs retained key features of pluripotency, but displayed decreased neural ectoderm coupled with enhanced mesoendoderm outcomes. Genome-wide analyses showed that E2A directly regulates neural ectoderm and Nodal pathway genes. Accordingly, inhibition of Nodal or E2A overexpression partially rescued the neural ectoderm defect in E2A KO hESCs. Loss of E2A had little impact on the epigenetic landscape of hESCs, whereas E2A KO neural precursors displayed increased accessibility of the gene locus encoding the Nodal agonist CRIPTO. Double-deletion of both E2A and HEB (TCF12) resulted in a more severe neural ectoderm defect. Therefore, this study reveals critical context-dependent functions for E2A in human neural ectoderm fate-specification.<\/jats:p>","DOI":"10.1242\/dev.190298","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T00:13:30Z","timestamp":1604448810000},"source":"Crossref","is-referenced-by-count":10,"title":["E2A regulates neural ectoderm fate specification in human embryonic stem cells"],"prefix":"10.1242","author":[{"given":"Siqi","family":"Yi","sequence":"first","affiliation":[{"name":"Department of Periodontology, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China"},{"name":"Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele K.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Z\u00fa\u00f1iga-Pfl\u00fccker","sequence":"additional","affiliation":[{"name":"Department of Immunology, University of Toronto, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingxian","family":"Luan","sequence":"additional","affiliation":[{"name":"Department of Periodontology, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8805-4980","authenticated-orcid":false,"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Basic Medical Sciences, Peking University Stem Cell Research Center, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2020,1,1]]},"reference":[{"key":"2021042700421429800_DEV190298C1","doi-asserted-by":"publisher","first-page":"4782","DOI":"10.1128\/MCB.17.8.4782","article-title":"E2A deficiency leads to abnormalities in alphabeta T-cell development and to rapid development of T-cell lymphomas","volume":"17","author":"Bain","year":"1997","journal-title":"Mol. 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