Myc represses transcription through recruitment of DNA methyltransferase corepressor

Abstract

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.

DNMT3A mutations in acute myeloid leukemia

“…However, it is possible that R882 mutations alter functions of DNMT3A that are not yet fully understood, including its ability to bind to other proteins involved in transcriptional regulation and localization to chromatin regions containing methylated DNA. [23][24][25][26] In any case, all DNMT3A mutations are associated with poor overall survival, suggesting that they have an important common effect on the potential of AML cells to cause lethal disease.…”

MYCN regulates oncogenic MicroRNAs in neuroblastoma

“…12 Recently, the Myc:Miz-1 complex was reported to also incorporate Dnmt3a, thereby, facilitating DNA methylation and constitutive transcriptional silencing. 11 Translational silencing mediated by MYCN induced miRNA upregulation is an independent additional mechanism by which MYCN could downregulate gene expression.…”

“…A complex of Myc and Miz-1 bound to the promoter leads to transcriptional silencing, at least in part by recruitment of Dnmt3a. 11,12 The mechanisms by which MYCN silences genes are currently less well understood than those for gene induction.…”

A novel MASH1 enhancer with N-myc and CREB-binding sites is active in neuroblastoma

“…Even closer to the initiation site there are CpG islands, possibly facilitating the binding of N-myc to the CACGCG motif. 9,28 However, transfection of N-myc into the neuroblastoma cell lines could not augment the MASH1 enhancer-promoter luciferase activity (result not shown). This unresponsiveness might be due to the abundant endogenous N-myc expressed in neuroblastoma.…”