The study by Fernandez et al. investigates the genomic targets of the human c-Myc protein, a transcription factor that regulates cellular responses to mitogenic signals. The authors used a large-scale screen to identify Myc-binding sites in live human cells, focusing on consensus DNA elements (CACGTG or E-boxes) located in the 5' regulatory regions of genes. They found that most promoter-associated E-boxes showed selective recovery with Myc, with a significant fraction (11%) of cellular loci bound by Myc at high frequencies. These high-affinity targets were highly conserved across different cell types and were bound independently of Myc expression levels. Overexpressed Myc associated with low-affinity targets and other sequences, suggesting non-specific binding. The strongest predictor of high-affinity targets was the location of E-boxes within CpG islands, which correlated with an open, preacetylated state of chromatin. Myc further enhanced histone acetylation, and in some cases, induced mRNA expression. The findings highlight the regulatory and biological diversity among Myc-target genes, emphasizing the complex interactions between Myc and chromatin structure.The study by Fernandez et al. investigates the genomic targets of the human c-Myc protein, a transcription factor that regulates cellular responses to mitogenic signals. The authors used a large-scale screen to identify Myc-binding sites in live human cells, focusing on consensus DNA elements (CACGTG or E-boxes) located in the 5' regulatory regions of genes. They found that most promoter-associated E-boxes showed selective recovery with Myc, with a significant fraction (11%) of cellular loci bound by Myc at high frequencies. These high-affinity targets were highly conserved across different cell types and were bound independently of Myc expression levels. Overexpressed Myc associated with low-affinity targets and other sequences, suggesting non-specific binding. The strongest predictor of high-affinity targets was the location of E-boxes within CpG islands, which correlated with an open, preacetylated state of chromatin. Myc further enhanced histone acetylation, and in some cases, induced mRNA expression. The findings highlight the regulatory and biological diversity among Myc-target genes, emphasizing the complex interactions between Myc and chromatin structure.