Alotaibi Hani, Basilicata M Felicia, Shehwana Huma, Kosowan Tyler, Schreck Ilona, Braeutigam Christien, Konu Ozlen, Brabletz Thomas, Stemmler Marc P
Department of Molecular Embryology, Max-Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany; Izmir Biomedicine and Genome Center, Dokuz Eylül University, Inciralti, 35340 Izmir, Turkey.
Department of Molecular Embryology, Max-Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany.
Biochim Biophys Acta. 2015 Jun;1849(6):731-42. doi: 10.1016/j.bbagrm.2015.01.005. Epub 2015 Jan 31.
Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) highlight crucial steps during embryogenesis and tumorigenesis. Induction of dramatic changes in gene expression and cell features is reflected by modulation of Cdh1 (E-cadherin) expression. We show that Cdh1 activity during MET is governed by two enhancers at +7.8 kb and at +11.5 kb within intron 2 that are activated by binding of Grhl3 and Hnf4α, respectively. Recruitment of Grhl3 and Hnf4α to the enhancers is crucial for activating Cdh1 and accomplishing MET in non-tumorigenic mouse mammary gland cells (NMuMG). Moreover, the two enhancers cooperate via Grhl3 and Hnf4α binding, induction of DNA-looping and clustering at the promoter to orchestrate E-cadherin re-expression. Our results provide novel insights into the cellular mechanisms whereby cells respond to MET signals and re-establish an epithelial phenotype by enhancer cooperativity. A general importance of our findings including MET-mediated colonization of metastasizing tumor cells is suggested.
上皮-间质转化（EMT）和间质-上皮转化（MET）是胚胎发育和肿瘤发生过程中的关键步骤。基因表达和细胞特征的显著变化通过Cdh1（E-钙黏蛋白）表达的调节得以体现。我们发现，MET过程中Cdh1的活性由位于第2内含子中+7.8 kb和+11.5 kb处的两个增强子控制，它们分别通过Grhl3和Hnf4α的结合而被激活。Grhl3和Hnf4α募集到增强子对于激活Cdh1以及在非致瘤性小鼠乳腺细胞（NMuMG）中完成MET至关重要。此外，这两个增强子通过Grhl3和Hnf4α的结合、DNA环化的诱导以及启动子处的聚集相互协作，以协调E-钙黏蛋白的重新表达。我们的研究结果为细胞响应MET信号并通过增强子协同作用重新建立上皮表型的细胞机制提供了新的见解。我们的发现包括MET介导的转移肿瘤细胞定植具有普遍重要性。
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