Article

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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    • "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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