"Myc represses transcription through recruitment of DNA methyltransferase corepressor"

The Myc transcription factor is an essential mediator of cell growth and proliferation through its ability to both positively and negatively regulate transcription. The mechanisms by which Myc silences gene expression are not well understood. The current model is that Myc represses transcription through functional interference with transcriptional activators. Here we show that Myc binds the corepressor Dnmt3a and associates with DNA methyltransferase activity in vivo. In cells with reduced Dnmt3a levels, we observe specific reactivation of the Myc-repressed p21Cip1 gene, whereas the expression of Mycactivated E-boxes genes is unchanged. In addition, we find that Myc can target Dnmt3a selectively to the promoter of p21Cip1. Myc is known to be recruited to the p21Cip1 promoter by the DNA-binding factor Miz-1. Consistent with this, we observe that Myc and Dnmt3a form a ternary complex with Miz-1 and that this complex can corepress the p21Cip1 promoter. Finally, we show that DNA methyla... Document type : Article de périodique (Journal article) Référence bibliographique Brenner, C ; Deplus, R ; Didelot, C ; Loriot, Axelle ; Vire, E ; et. al. Myc represses transcription through recruitment of DNA methyltransferase corepressor. In: The EMBO journal, Vol. 24, no. 2, p. 336-46 (2005) DOI : 10.1038/sj.emboj.7600509 Myc represses transcription through recruitment of DNA methyltransferase corepressor Carmen Brenner, Rachel Deplus, Céline Didelot, Axelle Loriot, Emmanuelle Viré, Charles De Smet, Arantxa Gutierrez, Davide Danovi, David Bernard, Thierry Boon, Pier Giuseppe Pelicci, Bruno Amati, Tony Kouzarides, Yvan de Launoit, Luciano Di Croce and François Fuks* Free University of Brussels, Faculty of Medicine, Laboratory of Molecular Virology, Brussels, Belgium, Ludwig Institute For Cancer Research, UCL, Brussels, Belgium, ICREA and Center for Genomic Regulation, Barcelona, Spain, Department of Experimental Oncology, European Institute of Oncology, Milan, Italy, Wellcome/Cancer Research UK Institute and Department of Pathology, University of Cambridge, Cambridge, UK and UMR 8117, CNRS Institut Pasteur de Lille, Université de Lille 1, Institut de Biologie de Lille, Lille, Cedex, France The Myc transcription factor is an essential mediator of cell growth and proliferation through its ability to both positively and negatively regulate transcription. The mechanisms by which Myc silences gene expression are not well understood. The current model is that Myc represses transcription through functional interference with transcriptional activators. Here we show that Myc binds the corepressor Dnmt3a and associates with DNA methyltransferase activity in vivo. In cells with reduced Dnmt3a levels, we observe specific reactivation of the Myc-repressed p21Cip1 gene, whereas the expression of Myc-activated E-boxes genes is unchanged. In addition, we find that Myc can target Dnmt3a selectively to the promoter of p21Cip1. Myc is known to be recruited to the p21Cip1 promoter by the DNA-binding factor Miz-1. Consistent with this, we observe that Myc and Dnmt3a form a ternary complex with Miz-1 and that this complex can corepress the p21Cip1 promoter. Finally, we show that DNA methylation is required for Myc-mediated repression of p21Cip1. Our data identify a new mechanism by which Myc can silence gene expression not only by passive functional interference but also by active recruitment of corepressor proteins. Furthermore, these findings suggest that targeting of DNA methyltransferases by transcription factors is a wide and general mechanism for the generation of specific DNA methylation patterns within a cell. The EMBO Journal (2005) 24, 336–346. doi:10.1038/ sj.emboj.7600509; Published online 16 December 2004 Subject Categories: chromatin & transcription

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