Browsing by Subject "Dna-binding proteins"

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    Enhancer cooperativity as a novel mechanism underlying the transcriptional regulation of E-cadherin during mesenchymal to epithelial transition
    (Elsevier, 2015) Alotaibi, H.; Basilicata, M. F.; Shehwana, H.; Kosowan, T.; Schreck, I.; Braeutigam, C.; Konu, O.; Brabletz, T.; Stemmler, M. P.
    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.