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Originally published In Press as doi:10.1074/jbc.M100265200 on February 20, 2001

J. Biol. Chem., Vol. 276, Issue 23, 20482-20490, June 8, 2001
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The Chromatin Structure of the Dual c-myc Promoter P1/P2 Is Regulated by Separate Elements*

Thomas AlbertDagger , Julie Wells§, Jens-Oliver Funk, Andrea Pullner, Eva-Elisabeth Raschke, Gertraud Stelzer||, Michael Meisterernst||, Peggy J. Farnham§, and Dirk Eick**

From the Institute of Clinical Molecular Biology and Tumor Genetics and || Department for Protein Chemistry, Research Centre for Environment and Health (GSF), Marchioninistrasse 25, D-81377 München, Germany and the § McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Madison, Wisconsin 53706

The proto-oncogene c-myc is transcribed from a dual promoter P1/P2, with transcription initiation sites 160 base pairs apart. Here we have studied the transcriptional activation of both promoters on chromatin templates. c-myc chromatin was reconstituted on stably transfected, episomal, Epstein-Barr virus-derived vectors in a B cell line. Episomal P1 and P2 promoters showed only basal activity but were strongly inducible by histone deacetylase inhibitors. The effect of promoter mutations on c-myc activity, chromatin structure, and E2F binding was studied. The ME1a1 binding site between P1 and P2 was required for the maintenance of an open chromatin configuration of the dual c-myc promoters. Mutation of this site strongly reduced the sensitivity of the core promoter region of P1/P2 to micrococcal nuclease and prevented binding of polymerase II (pol II) at the P2 promoter. In contrast, mutation of the P2 TATA box also abolished binding of pol II at the P2 promoter but did not affect the chromatin structure of the P1/P2 core promoter region. The E2F binding site adjacent to ME1a1 is required for repression of the P2 promoter but not the P1 promoter, likely by recruitment of histone deacetylase activity. Chromatin precipitation experiments with E2F-specific antibodies revealed binding of E2F-1, E2F-2, and E2F-4 to the E2F site of the c-myc promoter in vivo if the E2F site was intact. Taken together, the analyses support a model with a functional hierarchy for regulatory elements in the c-myc promoter region; binding of proteins to the ME1a1 site provides a nucleosome-free region of chromatin near the P2 start site, binding of E2F results in transcriptional repression without affecting polymerase recruitment, and the TATA box is required for polymerase recruitment.

* This work was supported by Die Deutsche Forschungsgemeinschaft (SFB190) and Fonds der Chemischen Industrie.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Lab. for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht University, P. O. Box 80042, 3508 TA Utrecht, The Netherlands.

Present address: Lab. of Molecular Tumor Biology, Dept. of Dermatology, University of Erlangen, 91052 Erlangen, Germany.

** To whom correspondence should be addressed: Institute of Clinical Molecular Biology and Tumor Genetics, GSF Research Centre, Marchioninistr. 25, D-81377 München, Germany. Tel.: +49-89-7099512; Fax: +49-89-7099500; E-mail: eick@gsf.de.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.


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