Enhancer cooperativity as a novel mechanism underlying the transcriptional regulation of E-cadherin during mesenchymal to epithelial transition.
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.
['Alotaibi|Hani|H|', 'Basilicata|M Felicia|MF|', 'Shehwana|Huma|H|', 'Kosowan|Tyler|T|', 'Schreck|Ilona|I|', 'Braeutigam|Christien|C|', 'Konu|Ozlen|O|', 'Brabletz|Thomas|T|', 'Stemmler|Marc P|MP|']
D000818:Animals D015820:Cadherins D002471:Cell Transformation, Neoplastic D004268:DNA-Binding Proteins D004742:Enhancer Elements, Genetic D058750:Epithelial-Mesenchymal Transition D015972:Gene Expression Regulation, Neoplastic D051557:Hepatocyte Nuclear Factor 4 D006801:Humans D051379:Mice D011401:Promoter Regions, Genetic D014157:Transcription Factors D014158:Transcription, Genetic
Grhl3 Hnf4α Cadherins Cancer Development Transforming growth factor beta