title: Genomic targets of the human c-Myc protein.
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.
authors.affiliation: DNAX Research Institute, Palo Alto, California 94304, USA.
authors.forename: Paula C
authors.initials: PC
authors.lastname: Fernandez
authors.forename: Scott R
authors.initials: SR
authors.lastname: Frank
authors.forename: Luquan
authors.initials: L
authors.lastname: Wang
authors.forename: Marianne
authors.initials: M
authors.lastname: Schroeder
authors.forename: Suxing
authors.initials: S
authors.lastname: Liu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Greene
authors.forename: Andrea
authors.initials: A
authors.lastname: Cocito
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands; D004247:DNA / Q000378:metabolism*; D024721:E-Box Elements; D005786:Gene Expression Regulation / Q000502:physiology; D015894:Genome, Human; D006657:Histones / Q000378:metabolism; D006801:Humans; D011233:Precipitin Tests; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D017422:Sequence Analysis, DNA
chemical_list: D002843:Chromatin; D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; D004247:DNA