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Updated: Aug 20, 2025
Induction of Mesenchymal-Epithelial Transitions in Sarcoma Cells
Published on: April 7, 2017
TBX1 targets the miR-200-ZEB2 axis to induce epithelial differentiation and inhibit stem cell properties
Noriko Funato1,2, Hiromi Yanagisawa3
1Department of Signal Gene Regulation, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510, Japan. noriko-funato@umin.ac.jp.
Abstract:
TBX1, which encodes a T-box transcription factor, is considered a candidate gene for DiGeorge syndrome, velocardiofacial syndrome, and conotruncal anomaly face syndrome. Transduction of TBX1 decreases cell proliferation in epithelial cancer cells and Tbx1 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 miR-200b/200a/429 cluster, whose promoter region contains conserved overlapping cis-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, BMI1 and ZEB2. Moreover, Tbx1 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-miR-200 axis by TBX1 may have potential therapeutic implications in miR-200-associated tumors and cleft palate.
Insights
TBX1 transcription factor regulates stem cell properties and epithelial differentiation by activating microRNAs, including miR-200 and miR-203. This pathway has therapeutic potential for tumors and cleft palate.
Area of Science:
- Developmental Biology
- Molecular Biology
- Genetics
Background:
- TBX1 is a candidate gene for DiGeorge, velocardiofacial, and conotruncal anomaly face syndromes.
- TBX1 influences cell proliferation and epithelial development, with roles in both cancer and embryonic palatal formation.
Purpose of the Study:
- To investigate the role of TBX1 in regulating stem cell properties and epithelial differentiation.
- To elucidate the molecular mechanisms by which TBX1 exerts its effects on microRNA expression and target genes.
Main Methods:
- Analyzing the effect of TBX1 expression and ablation on microRNA expression (miR-200, miR-203) in epithelial cells.
- Investigating the regulation of the miR-200b/200a/429 cluster promoter by TBX1 and ZEB2.
- Assessing the impact of Tbx1 ablation on palatal epithelial differentiation and gene expression.
Main Results:
- TBX1 induces miR-200 expression, which represses the epithelial-to-mesenchymal transition and promotes epithelial differentiation.
- TBX1 activates miR-203, a stemness inhibitor, and both microRNAs target BMI1 and ZEB2.
- Tbx1 ablation disrupts palatal epithelial differentiation and alters the expression of miR-200, miR-203, and their targets.
Conclusions:
- TBX1 acts as a key regulator of stemness and epithelial differentiation through the transcriptional induction of miR-200 and miR-203.
- The TBX1-ZEB2-miR-200 axis is a critical pathway in epithelial development and homeostasis.
- Targeting this pathway holds therapeutic promise for miR-200-related cancers and cleft palate development.
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