Enhancer cooperativity as a novel mechanism underlying the transcriptional regulation of E-cadherin during mesenchymal to epithelial transition.

Autor: Alotaibi, Hani, Basilicata, M. Felicia, Shehwana, Huma, Kosowan, Tyler, Schreck, Ilona, Braeutigam, Christien, Konu, Ozlen, Brabletz, Thomas, Stemmler, Marc P.
Zdroj: BBA - Gene Regulatory Mechanisms; Jun2015, Vol. 1849 Issue 6, p731-742, 12p
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
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