Myc represses transcription through recruitment of DNA methyltransferase corepressor

被引:322
作者
Brenner, C
Deplus, R
Didelot, C
Loriot, A
Viré, E
De Smet, C
Gutierrez, A
Danovi, D
Bernard, D
Boon, T
Pelicci, PG
Amati, B
Kouzarides, T
de Launoit, Y
Di Croce, L
Fuks, F
机构
[1] Free Univ Brussels, Fac Med, Mol Virol Lab, B-1070 Brussels, Belgium
[2] UCL, Ludwig Inst Canc Res, Brussels, Belgium
[3] ICREA, Barcelona, Spain
[4] Ctr Gen Regulat, Barcelona, Spain
[5] European Inst Oncol, Dept Expt Oncol, Milan, Italy
[6] Wellcome Canc Res UK Inst, Cambridge, England
[7] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England
[8] Univ Lille 1, Inst Biol Lille, CNRS, Inst Pasteur Lille,UMR 8117, Lille, France
关键词
DNA methylation; Dnmt3a; Myc; transcriptional repression;
D O I
10.1038/sj.emboj.7600509
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:336 / 346
页数:11
相关论文
共 51 条
[21]   TATA-BINDING PROTEIN AND THE RETINOBLASTOMA GENE-PRODUCT BIND TO OVERLAPPING EPITOPES ON C-MYC AND ADENOVIRUS E1A PROTEIN [J].
HATEBOER, G ;
TIMMERS, HTM ;
RUSTGI, AK ;
BILLAUD, M ;
VANTVEER, LJ ;
BERNARDS, R .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (18) :8489-8493
[22]  
Herman JG, 1996, CANCER RES, V56, P722
[23]   Negative regulation of the mammalian UV response by Myc through association with Miz-1 [J].
Herold, S ;
Wanzel, M ;
Beuger, V ;
Frohme, C ;
Beul, D ;
Hillukkala, T ;
Syvaoja, J ;
Saluz, HP ;
Haenel, F ;
Eilers, M .
MOLECULAR CELL, 2002, 10 (03) :509-521
[24]  
Hsieh CL, 1999, MOL CELL BIOL, V19, P8211
[25]  
Izumi H, 2001, J CELL SCI, V114, P1533
[26]   Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase [J].
Jackson, JP ;
Lindroth, AM ;
Cao, XF ;
Jacobsen, SE .
NATURE, 2002, 416 (6880) :556-560
[27]   Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals [J].
Jaenisch, R ;
Bird, A .
NATURE GENETICS, 2003, 33 (Suppl 3) :245-254
[28]   Histone methylation in transcriptional control [J].
Kouzarides, T .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 2002, 12 (02) :198-209
[29]   Histone acetylation and deacetylation in yeast [J].
Kurdistani, SK ;
Grunstein, M .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2003, 4 (04) :276-284
[30]   Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin [J].
Lehnertz, B ;
Ueda, Y ;
Derijck, AAHA ;
Braunschweig, U ;
Perez-Burgos, L ;
Kubicek, S ;
Chen, TP ;
Li, E ;
Jenuwein, T ;
Peters, AHFM .
CURRENT BIOLOGY, 2003, 13 (14) :1192-1200