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Transduction of TBX1 decreases cell proliferation in epithelial cancer cells and <jats:italic>Tbx1<\/jats:italic> ablation induces epithelial proliferation during palatal development. Here, we report that TBX1 regulates stem cell properties and epithelial differentiation through the transcriptional activation of microRNAs. Stable expression of TBX1 induces microRNA-200 (miR-200), whose members repress the epithelial-to-mesenchymal transition and induce epithelial differentiation. TBX1 rescues ZEB2-dependent transcriptional inhibition of the <jats:italic>miR-200b\/200a\/429<\/jats:italic> cluster, whose promoter region contains conserved overlapping <jats:italic>cis<\/jats:italic>-regulatory motifs of the ZEB-binding E-box and TBX-binding element. Consequently, TBX1 activates the expression of both miR-200 and stemness-inhibitor miR-203 to inhibit their common targets, <jats:italic>BMI1<\/jats:italic> and <jats:italic>ZEB2<\/jats:italic>. Moreover, <jats:italic>Tbx1<\/jats:italic> ablation affects the differentiation of the palatal epithelium and perturbs the expression of miR-200, miR-203, and their target genes. We propose that TBX1 links stem cell properties and epithelial differentiation by inducing miR-200 and miR-203. Thus, targeting of the ZEB2\u2013miR-200 axis by TBX1 may have potential therapeutic implications in miR-200-associated tumors and cleft palate.<\/jats:p>","DOI":"10.1038\/s41598-022-24604-9","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T17:57:49Z","timestamp":1669312669000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["TBX1 targets the miR-200\u2013ZEB2 axis to induce epithelial differentiation and inhibit stem cell properties"],"prefix":"10.1038","volume":"12","author":[{"given":"Noriko","family":"Funato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiromi","family":"Yanagisawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"24604_CR1","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1016\/S0140-6736(03)14632-6","volume":"362","author":"H Yagi","year":"2003","unstructured":"Yagi, H. et al. 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