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

doi:10.1073/pnas.1332764100

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

^*Ludwig Institute for Cancer Research and Departments of ^§Cellular and Molecular Medicine and ^†Medicine, University of California at San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0653; and ^‡Cold Spring Harbor Laboratory, 1 Bungtown Road, P.O. Box 100, Cold Spring Harbor, NY 11724

Communicated by Thomas Maniatis, Harvard University, Cambridge, MA, May 8, 2003 (received for review March 24, 2003)

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.

Footnotes

↵ ¶ To whom correspondence should be addressed. E-mail: biren{at}ucsd.edu.
Abbreviations: pol, RNA polymerase; TF, transcription factor; hu6K, DNA microarray of ≈6,000 human genomic DNA fragments; ChIP, chromatin immunoprecipitation.