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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2019,8,27]]},"abstract":"<jats:p>Mutations in transcription factor p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. The underlying cellular and molecular mechanism is however not yet understood. We established an epidermal commitment model using human induced pluripotent stem cells (iPSCs) and characterized differentiation defects of iPSCs derived from ectrodactyly, ectodermal dysplasia, and cleft lip\/palate (EEC) syndrome patients carrying p63 mutations. Transcriptome analyses revealed stepwise cell fate transitions during epidermal commitment: Specification from multipotent simple epithelium to basal stratified epithelia and ultimately to the mature epidermal fate. Differentiation defects of EEC iPSCs caused by p63 mutations occurred during the specification switch from the simple epithelium to the basal-stratified epithelial fate. Single-cell transcriptome and pseudotime analyses of cell states identified mesodermal activation that was associated with the deviated commitment route of EEC iPSCs. Integrated analyses of differentially regulated genes and p63-dependent dynamic genomic enhancers during epidermal commitment suggest that p63 directly controls epidermal gene activation at the specification switch and has an indirect effect on mesodermal gene repression. Importantly, inhibitors of mesodermal induction enhanced epidermal commitment of EEC iPSCs. Our findings demonstrate that p63 is required for specification of stratified epithelia, and that epidermal commitment defects caused by p63 mutations can be reversed by repressing mesodermal induction. This study provides insights into disease mechanisms underlying stratified epithelial defects caused by p63 mutations and suggests potential therapeutic strategies for the disease.<\/jats:p>","DOI":"10.1073\/pnas.1908180116","type":"journal-article","created":{"date-parts":[[2019,8,14]],"date-time":"2019-08-14T19:45:26Z","timestamp":1565811926000},"page":"17361-17370","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":22,"title":["Single-cell RNA-seq identifies a reversible mesodermal activation in abnormally specified epithelia of p63 EEC syndrome"],"prefix":"10.1073","volume":"116","author":[{"given":"Eduardo","family":"Soares","sequence":"first","affiliation":[{"name":"Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, 6525GA Nijmegen, The Netherlands;"},{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior (CAPES) Foundation, Ministry of Education of Brazil, 70.040-031 Bras\u00edlia, Brazil;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, 6525GA Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingqing","family":"Li","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Genomics, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking University, 100871 Beijing, China;"},{"name":"Biomedical Pioneering Innovation Center, Peking University, 100871 Beijing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieqiong","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, 6525GA Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Zheng","sequence":"additional","affiliation":[{"name":"Beijing Advanced Innovation Center for Genomics, Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking University, 100871 Beijing, China;"},{"name":"Biomedical Pioneering Innovation Center, Peking University, 100871 Beijing, China;"},{"name":"Peking-Tsinghua Center for Life Sciences, Peking University, 100871 Beijing, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henriette H. 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