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Vol. 17, No. 9, pp. 1115-1129, May 1, 2003
1 DNAX Research Institute, Palo Alto, California 94304, USA; 2 Schering-Plough Research Institute, Kenilworth, New
Jersey 07033, USA; 3 Department of Experimental Oncology,
European Institute of Oncology, 20141 Milan, Italy
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.
[Keywords: Human; genome; chromatin; transcription factor; Myc]
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A. Blais |
