Abstract
Myc is a transcription factor that features prominently in cancer. The oncogenicity of Myc stems from its ability to regulate expression of genes required for cell growth and proliferation. Although the mechanisms through which Myc activates transcription have been extensively studied, less is known about how Myc represses transcription. Recently, we reported that a conserved element within Myc-MbIII- is important for transcriptional repression. Here, we investigate the mechanism through which MbIII contributes to repression. We show that Myc represses transcription of target genes Id2 and Gadd153 by a process that involves histone deacetylation. We show that MbIII is important for repression of these genes and present evidence that this element contributes to repression by recruiting the histone deacetylase HDAC3 to the Id2 and Gadd153 promoters. These results describe a mechanistic role for MbIII in transcription, and reveal that recruitment of HDAC3 is a process by which Myc represses gene activity.
Highlights
Myc is a helix-loop-helix transcription factor that regulates cell growth and proliferation [1]
Myc was initially described as a transcriptional activator, subsequent studies have shown that the ability of Myc to repress transcription is critical for its function in normal and cancer states [1]
Using the Gadd153 and Id2 genes as platforms for our analyses, we have found that: (a) repression of these genes by Myc is associated with a loss of histone H4 acetylation; (b) histone deacetylase (HDAC) activity, from HDAC3, contributes to repression; (c) Myc recruits HDAC3 to these genes in an Myc box III (MbIII)-dependent manner; and (d) the functional interaction of Myc with HDAC3 plays an important role in the ability of Myc to promote apoptosis
Summary
Myc is a helix-loop-helix transcription factor that regulates cell growth and proliferation [1]. Because the amino terminus of Myc contains a potent transcriptional activation domain, initial studies on Myc focused on its role as a transcriptional activator. These studies revealed that the ability of Myc to recruit histone acetyltransferases (HAT) to chromatin is crucial for transcriptional activation and led to the notion that Myc acts as a ‘‘permissive factor’’, stimulating gene activity by creating a chromatin environment that is conducive for gene induction [2]. Despite the initial focus on activation, subsequent studies revealed that Myc-driven transcriptional repression is critical for its oncogenic activity [1].
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