Genomic targets of the human c-Myc protein. Genes Dev

DNAX Research Institute, Palo Alto, California 94304, USA.
Genes & Development (Impact Factor: 12.64). 06/2003; 17(9):1115-29. DOI: 10.1101/gad.1067003
Source: PubMed

ABSTRACT The transcription factor Myc is induced by mitogenic signals and regulates downstream cellular responses. If overexpressed, Myc promotes malignant transformation. Myc modulates expression of diverse genes in experimental systems, but few are proven direct targets. Here, we present a large-scale screen for genomic Myc-binding sites in live human cells. We used bioinformatics to select consensus DNA elements (CACGTG or E-boxes) situated in the 5' regulatory region of genes and measured Myc binding to those sequences in vivo by quantitative chromatin immunoprecipitation. Strikingly, most promoter-associated E-boxes showed selective recovery with Myc, unlike non-E-box promoters or E-boxes in bulk genomic DNA. Promoter E-boxes were distributed in two groups bound by Myc at distinct frequencies. The high-affinity group included an estimated 11% of all cellular loci, was highly conserved among different cells, and was bound independently of Myc expression levels. Overexpressed Myc associated at increased frequency with low-affinity targets and, at extreme levels, also with other sequences, suggesting that some binding was not sequence-specific. The strongest DNA-sequence parameter defining high-affinity targets was the location of E-boxes within CpG islands, correlating with an open, preacetylated state of chromatin. Myc further enhanced histone acetylation, with or without accompanying induction of mRNA expression. Our findings point to a high regulatory and biological diversity among Myc-target genes.

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    • "Similarly, in our study, the enhanced expression level of FoxD3 by colonies formed in higher percentages of EE indicated achievement of better reprogramming, as FoxD3 plays a crucial role in repressing differentiation, promoting self-renewal and maintaining survival of ESC (Liu and Labosky, 2008). c-Myc helps in expression and maintenance of pluripotency factors through global histone acetylation in the mammalian genome and expression of TIP-110 (Tat interacting protein of 110 kDa) in ESC (Fernandez et al., 2003; Liu et al., 2013). It is now known that c-Myc only helps in enhancing, but not a necessary factor for reprogramming (Zhao et al., 2010). "
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    ABSTRACT: An attempt was made to study the efficiency of chicken (Gallus gallus domesticus) egg extract (EE) to reprogram buffalo (Bubalus bubalis) foetal fibroblasts (bFFs) without incorporation of ectopic transcription factors. The isolated bFFs were cultured in media supplemented with 2%, 4%, 6% and 10% EE to induce reprogramming. It was observed that fewer but larger sized alkaline phosphatase positive (AP(+ve)) colonies developed in culture system containing 2% EE whereas, more but smaller sized colonies developed in 4%, 6% and 10% EE. The developed colonies expressed pluripotency markers like Oct4, Nanog, SSEA1, TRA-1-60, TRA-1-81 and RT-PCR study revealed relative expression of genes indicating pluripotency (Oct4, Sox2, Nanog and FoxD3) increased as the concentration of EE increased in culture systems confirming the reprogramming capability of chicken EE.
    Research in Veterinary Science 02/2014; 96(2). DOI:10.1016/j.rvsc.2014.02.008 · 1.51 Impact Factor
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    • "The Myc oncoproteins are deregulated in the majority of human cancers [1]. It has been shown that Myc/Max heterodimers interact with 10–15% of human promoters and target already active or potentially active, i.e. preset, chromatin by binding preferentially to promoters carrying histone H3K9 and H3K18 acetylation marks as well as di-and tri-methylations of H3K4 and di-methylation of H3K79 [3] [4] [5] [6] [7] [8]. In this study, we have used the Xenopus oocyte model, which allows in vivo chromatin and transcriptional studies of a reconstituted promoter at high precision . "
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    ABSTRACT: The transcription factors c-Myc and Mnt regulate gene expression through dimerization with Max and binding to E-boxes in target genes. While c-Myc activates gene expression via recruitment of histone modifying complexes Mnt acts as a transcriptional repressor. Here, we used the Xenopus leavis oocyte system to address the effect of c-Myc and Mnt on transcription and chromatin remodeling over the E-box region in the human telomerase reverse transcriptase (hTERT) promoter. As expected we found elevated and decreased levels of hTERT transcription upon exogenously expressed c-Myc/Max and Mnt/Max, respectively. In addition, we confirmed binding of these heterodimers to both E-boxes already enriched with H3K9ac and H4K16ac. These marks were further enhanced upon c-Myc/Max binding followed by increased DNA accessibility in the E-box region. In contrast, Mnt/Max inhibited Myc-induced transcription and mediated repression through complete chromatin condensation and deacetylation of H3K9 and H4K16 across the E-box region. Importantly, Mnt was able to counteract c-Myc mediated activation even when expressed at low levels, suggesting Mnt to act as a strong repressor by closing the chromatin structure. Collectively our data demonstrate that the balance between c-Myc and Mnt activity determines the transcriptional outcome of the hTERT promoter by modulation of the chromatin architecture.
    Experimental Cell Research 07/2013; 319(20). DOI:10.1016/j.yexcr.2013.07.004 · 3.37 Impact Factor
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    • "To investigate the relationship between c-Myc levels and c- Myc genome occupancy in P493-6 cells, we used chromatin immunoprecipitation coupled to high-throughput sequencing (ChIP-Seq) with antibodies specific for c-Myc at 0, 1, and 24 hr after MYC induction. Previous studies have shown that c-Myc tends to occupy the promoter regions of protein-coding genes (Chen et al., 2008; Fernandez et al., 2003; Guccione et al., 2006; Kidder et al., 2008; Li et al., 2003; Rahl et al., 2010; Zeller et al., 2006), so we focused our initial analysis on the 2 kb regions surrounding the transcription start sites of such genes. The results showed that c-Myc generally occupies the core promoters of actively transcribed genes, as evidenced by cooccupancy with RNA Pol II (Figure 1E). "
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    ABSTRACT: Elevated expression of the c-Myc transcription factor occurs frequently in human cancers and is associated with tumor aggression and poor clinical outcome. The effect of high levels of c-Myc on global gene regulation is poorly understood but is widely thought to involve newly activated or repressed "Myc target genes." We report here that in tumor cells expressing high levels of c-Myc the transcription factor accumulates in the promoter regions of active genes and causes transcriptional amplification, producing increased levels of transcripts within the cell's gene expression program. Thus, rather than binding and regulating a new set of genes, c-Myc amplifies the output of the existing gene expression program. These results provide an explanation for the diverse effects of oncogenic c-Myc on gene expression in different tumor cells and suggest that transcriptional amplification reduces rate-limiting constraints for tumor cell growth and proliferation.
    Cell 09/2012; 151(1):56-67. DOI:10.1016/j.cell.2012.08.026 · 33.12 Impact Factor
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