title: Enhancer cooperativity as a novel mechanism underlying the transcriptional regulation of E-cadherin during mesenchymal to epithelial transition.
abstract: 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.
authors: 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.
authors: Hani
authors: H
authors: Alotaibi
authors: Department of Molecular Embryology, Max-Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany.
authors: M Felicia
authors: MF
authors: Basilicata
authors: Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
authors: Huma
authors: H
authors: Shehwana
authors: Department of Molecular Embryology, Max-Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany.
authors: Tyler
authors: T
authors: Kosowan
authors: Department of Molecular Embryology, Max-Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany.
authors: Ilona
authors: I
authors: Schreck
authors: Department of Molecular Embryology, Max-Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany.
authors: Christien
authors: C
authors: Braeutigam
authors: Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
authors: Ozlen
authors: O
authors: Konu
authors: Department of Visceral Surgery, University Medical Center Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Comprehensive Cancer Center Freiburg, University Medical Center Freiburg, D-79106 Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, D-79104 Freiburg, Germany; Institute of Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, D-91054 Erlangen, Germany.
authors: Thomas
authors: T
authors: Brabletz
authors: Department of Molecular Embryology, Max-Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany; Department of Visceral Surgery, University Medical Center Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany; Institute of Experimental Medicine I, Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nürnberg, D-91054 Erlangen, Germany. Electronic address: marc.stemmler@fau.de.
authors: Marc P
authors: MP
authors: Stemmler
mesh_terms: D000818:Animals; D015820:Cadherins / Q000096:biosynthesis* / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D004742:Enhancer Elements, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; C499942:Grhl3 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D014157:Transcription Factors
keywords: Cadherins; Cancer; Development; Grhl3; Hnf4α; Transforming growth factor beta