Alotaibi, H.Basilicata, M. F.Shehwana, H.Kosowan, T.Schreck, I.Braeutigam, C.Konu, O.Brabletz, T.Stemmler, M. P.2016-02-082016-02-0820151874-9399http://hdl.handle.net/11693/23170Epithelial-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.EnglishCadherinsCancerDevelopmentGrhl3Hnf4αTransforming growth factor betaCadherinsDna-binding proteinsGrhl3 proteinHepatocyte Nuclear Factor 4Hnf4a proteinTranscription FactorsAnimalsBiosynthesisCell transformationEnhancer elementsEpithelial-mesenchymal transitionGene Expression RegulationGeneticsHumansMicePromoter RegionsTranscriptionAnimalsCadherinsCell TransformationDNA-Binding ProteinsEnhancer ElementsEpithelial-Mesenchymal TransitionGene Expression RegulationHepatocyte Nuclear Factor 4HumansMicePromoter RegionsTranscription FactorsTranscriptionArticle10.1016/j.bbagrm.2015.01.005