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 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.
Brenner
Carmen
C
Free University of Brussels, Faculty of Medicine, Laboratory of Molecular Virology, Brussels, Belgium.
Deplus
Rachel
R
Didelot
Céline
C
Loriot
Axelle
A
Viré
Emmanuelle
E
De Smet
Charles
C
Gutierrez
Arantxa
A
Danovi
Davide
D
Bernard
David
D
Boon
Thierry
T
Pelicci
Pier Giuseppe
PG
Amati
Bruno
B
Kouzarides
Tony
T
de Launoit
Yvan
Y
Di Croce
Luciano
L
Fuks
François
F
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000090205:DNA Methyltransferase 3A; D017931:DNA Primers; D020868:Gene Silencing / Q000502:physiology; D047468:Immunoprecipitation; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology*
C493958:Cdkn1a protein, rat; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D016271:Proto-Oncogene Proteins c-myc; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A