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. 2003 Jul 8;100(14):8164-9.
doi: 10.1073/pnas.1332764100. Epub 2003 Jun 13.

A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells

Zirong Li  1 , Sara Van Calcar, Chunxu Qu, Webster K Cavenee, Michael Q Zhang, Bing Ren
Affiliations

A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells

Zirong Li et al. Proc Natl Acad Sci U S A. .

Abstract

Overexpression of c-Myc is one of the most common alterations in human cancers, yet it is not clear how this transcription factor acts to promote malignant transformation. To understand the molecular targets of c-Myc function, we have used an unbiased genome-wide location-analysis approach to examine the genomic binding sites of c-Myc in Burkitt's lymphoma cells. We find that c-Myc together with its heterodimeric partner, Max, occupy >15% of gene promoters tested in these cancer cells. The DNA binding of c-Myc and Max correlates extensively with gene expression throughout the genome, a hallmark attribute of general transcription factors. The c-Myc/Max heterodimer complexes also colocalize with transcription factor IID in these cells, further supporting a general role for overexpressed c-Myc in global gene regulation. In addition, transcription of a majority of c-Myc target genes exhibits changes correlated with levels of c-myc mRNA in a diverse set of tissues and cell lines, supporting the conclusion that c-Myc regulates them. Taken together, these results suggest a general role for overexpressed c-Myc in global transcriptional regulation in some cancer cells and point toward molecular mechanisms for c-Myc function in malignant transformation.

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Figures

Fig. 1.
Fig. 1.
Genome-wide location analysis of c-Myc- and Max-bound promoters in Burkitt's lymphoma cells. Five independent experiments were performed to identify c-Myc or Max bound DNA in formaldehyde-crosslinked Daudi cells. (A) A scatter plot showing the fluorescent intensities for each spot on the hu6K promoter array in one of the c-Myc location-analysis experiments. A few previously known c-Myc target genes are highlighted. (B and C) Scatter plots corresponding to one of the Max location-analysis experiments, or the control experiment, in which ChIP was performed in the absence of primary antibodies. (D) Venn diagram comparing the DNA binding of c-Myc and Max. The data from five experiments were averaged (see Methods), and the genes with a P value <0.001 were counted as targets. Overall, 876 and 931 promoters are bound by c-Myc and Max, respectively. Marked with red in A–C are 776 promoters that are bound by both. (E) A comparison of the fraction of promoter or coding regions represented on the hu6K array that are bound by c-Myc, Max, or both in Daudi cells. (F) Conventional ChIP confirms the enrichment of c-Myc/Max target genes identified in the genome-wide location-analysis experiments. ChIP was performed with chromatin from Daudi cells by using the indicated primary antibodies, and enriched DNA was amplified with primers corresponding to a random select number of genes. As a negative control, magnetic beads lacking primary antibodies were used.
Fig. 2.
Fig. 2.
DNA binding of c-Myc and Max corresponds to genome transcription levels and resembles the behavior of a general transcription factor. (A) Line chart showing the correlation between gene-expression levels and promoter binding by c-Myc, Max, pol II, and E2F1 in Daudi cells. The 4,839 gene promoters in the hu6K arrays were divided into 17 groups based on their transcription activities (see Supporting Data Set for Fig. 2, which is published as supporting information on the PNAS web site). The lower and upper boundaries of log10-transformed gene-expression values for these groups are distributed evenly between -1 and 5. The fraction of promoters bound by each factor in every group is plotted with regard to the log10-transformed transcription activity for the group. (B) Table showing the pairwise comparison of genomic binding profiles of c-Myc, Max, pol II, and E2F1 with respect to genome expression. P values were calculated based on two-factor ANOVA analysis without replicate.
Fig. 3.
Fig. 3.
c-Myc and Max colocalize with TFIID in Burkitt's lymphoma cells. A Venn diagram compares the gene promoters bound by the c-Myc/Max complexes and that by TFIID in Daudi cells.
Fig. 4.
Fig. 4.
Expression of c-Myc/Max target genes correlates with levels of c-myc transcript in human tissues and cell lines. (Left) Two-way clustering was performed on the expression data corresponding to 453 c-Myc/Max target genes in 46 human tissues and cell lines. The expression data for each gene were log-transformed and normalized such that the median log expression value is 0. The gene-expression values were represented by using a red-green color scheme, with red corresponding to higher-than-median expression values and green corresponding to lower-than-median expression values. The expression data corresponding to different genes are arranged from left to right, and different tissues are arranged from top to bottom. (Right) The c-myc mRNA levels in the corresponding samples, as measured by using Affymetrix GeneChip, are shown on a bar graph.
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