TRRAP and GCN5 are used by c-Myc to activate RNA polymerase III transcription
ABSTRACT Activation of RNA polymerase (pol) II transcription by c-Myc generally involves recruitment of histone acetyltransferases and acetylation of histones H3 and H4. Here, we describe the mechanism used by c-Myc to activate pol III transcription of tRNA and 5S rRNA genes. Within 2 h of its induction, c-Myc appears at these genes along with the histone acetyltransferase GCN5 and the cofactor TRRAP. At the same time, occupancy of the pol III-specific factor TFIIIB increases and histone H3 becomes hyperacetylated, but increased histone H4 acetylation is not detected at these genes. The rapid acetylation of histone H3 and promoter assembly of TFIIIB, c-Myc, GCN5, and TRRAP are followed by recruitment of pol III and transcriptional induction. The selective acetylation of histone H3 distinguishes pol III activation by c-Myc from mechanisms observed in other systems.
Full-textDOI: · Available from: Natividad Gomez-Roman, Jul 02, 2014
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ABSTRACT: Myc deregulation is a hallmark oncogenic event where overexpression of the transcription factor gives rise to numerous tumorigenic phenotypes. The complex consequences of Myc deregulation have prevented clear mechanistic interpretations of its function. A synthesis of recent experimental observations offers a consensus on the direct transcriptional function of Myc: when overexpressed, Myc broadly engages the established euchromatic cis-regulatory landscape of the cell, where the factor generally amplifies transcription. The level of Myc binding at target genes and the transcriptional output are differentially modulated by additional regulators, including Miz1. Targeting Myc oncogenic activity will require an understanding of whether amplification promotes tumorigenesis and the consequences of amplification in tumors adapted to oncogenic Myc. Copyright © 2014 Elsevier Ltd. All rights reserved.Trends in Cell Biology 12/2014; DOI:10.1016/j.tcb.2014.10.006 · 12.31 Impact Factor
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ABSTRACT: The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction.Translational Psychiatry 10/2014; 4:e473. DOI:10.1038/tp.2014.107 · 4.36 Impact Factor