Fernandez, P. C. et al. Genomic targets of the human c-Myc protein. Genes Dev. 17, 1115-1129

DNAX Research Institute, Palo Alto, California 94304, USA.
Genes & Development (Impact Factor: 10.8). 06/2003; 17(9):1115-29. DOI: 10.1101/gad.1067003
Source: PubMed


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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    • "These results are supported by the report from Yustein et al. that described JAG2 as one of the MYC target genes participating in tumorigenesis in a human B cell model [34]. Together with a study describing NOTCH4 as a MYC target [35], these two reports represent the only experimental evidence, to our knowledge, for transcriptional control of the NOTCH pathway by MYC. "
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    ABSTRACT: Medulloblastoma (MB), the most common pediatric malignant brain cancer, typically arises as pathological result of deregulated developmental pathways, including the NOTCH signaling cascade. Unlike the evidence supporting a role for NOTCH receptors in MB development, the pathological functions of NOTCH ligands remain largely unexplored. By examining the expression in large cohorts of MB primary tumors, and in established in vitro MB models, this research study demonstrates that MB cells bear abnormal levels of distinct NOTCH ligands. We explored the potential association between NOTCH ligands and the clinical outcome of MB patients, and investigated the rational of inhibiting NOTCH signaling by targeting specific ligands to ultimately provide therapeutic benefits in MB. The research revealed a significant over-expression of ligand JAG1 in the vast majority of MBs, and proved that JAG1 mediates pro-proliferative signals via activation of NOTCH2 receptor and induction of HES1 expression, thus representing an attractive therapeutic target. Furthermore, we could identify a clinically relevant association between ligand JAG2 and the oncogene MYC, specific for MYC-driven Group 3 MB cases. We describe for the first time a mechanistic link between the oncogene MYC and NOTCH pathway in MB, by identifying JAG2 as MYC target, and by showing that MB cells acquire induced expression of JAG2 through MYC-induced transcriptional activation. Finally, the positive correlation of MYC and JAG2 also with aggressive anaplastic tumors and highly metastatic MB stages suggested that high JAG2 expression may be useful as additional marker to identify aggressive MBs.
    Full-text · Article · Apr 2014
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    • "In Myc-related cancers, Myc is constitutively expressed and leads to the abnormal expression of many genes which may be involved in cell proliferation, differentiation and apoptosis, and these uncontrolled biological processes finally underlie the cancer. Myc is believed to regulate expression of 15% of all genes [77]. Similar with CCND1, Myc expression could be regulated transcriptionally, posttranscriptionally, or posttranslationally [78]. "
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    ABSTRACT: Gastric cancer, as one of the leading causes of cancer related deaths worldwide, causes about 800,000 deaths per year. Up to now, the mechanism underlying this disease is still not totally uncovered. Identification of related genes of this disease is an important step which can help to understand the mechanism underlying this disease, thereby designing effective treatments. In this study, some novel gastric cancer related genes were discovered based on the knowledge of known gastric cancer related ones. These genes were searched by applying the shortest path algorithm in protein-protein interaction network. The analysis results suggest that some of them are indeed involved in the biological process of gastric cancer, which indicates that they are the actual gastric cancer related genes with high probability. It is hopeful that the findings in this study may help promote the study of this disease and the methods can provide new insights to study various diseases.
    Full-text · Article · Mar 2014
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    • "It has been previously shown that overexpressed Myc could associate with low-affinity targets at an increased frequency and, at even higher levels, with other sequences [24] [25]. Motif discovery analysis of Bio-Myc, Max, and Myc ChIP-Seq analyses showed that all three ChIP-Seq datasets are enriched for a DNA sequence containing the perfect E-Box sequence CACGTG with high p-values: Bio-Myc 1E-205, Myc 1E-255, and Max 1E-588 (Figure 3A). "
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    ABSTRACT: Myc is a master transcription factor that has been demonstrated to be required for embryonic stem cell (ESC) pluripotency, self-renewal, and inhibition of differentiation. Although recent works have identified several Myc-targets in ESCs, the list of Myc binding sites is largely incomplete due to the low sensitivity and specificity of the antibodies available. To systematically identify Myc binding sites in mouse ESCs, we used a stringent streptavidin-based genome-wide chromatin immunoprecipitation (ChIP-Seq) approach with biotin-tagged Myc (Bio-Myc) as well as a ChIP-Seq of the Myc binding partner Max. This analysis identified 4325 Myc binding sites, of which 2885 were newly identified. The identified sites overlap with more than 85% of the Max binding sites and are enriched for H3K4me3-positive promoters and active enhancers. Remarkably, this analysis unveils that Myc/Max regulates chromatin modifiers and transcriptional regulators involved in stem cell self-renewal linking the Myc-centered network with the Polycomb and the Core networks. These results provide insights into the contribution of Myc and Max in maintaining stem cell self-renewal and keeping these cells in an undifferentiated state.
    Full-text · Article · Feb 2014 · PLoS ONE
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