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Molecular and Cellular Biology, May 2005, p. 3923-3933, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.3923-3933.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Chromatin Inactivation Precedes De Novo DNA Methylation during the Progressive Epigenetic Silencing of the RASSF1A Promoter{dagger}

Maria Strunnikova,1 Undraga Schagdarsurengin,1 Astrid Kehlen,2 James C. Garbe,3 Martha R. Stampfer,3 and Reinhard Dammann1*

AG Tumorgenetik der Medizinischen Fakultät, Martin-Luther-Universität Halle-Wittenberg, 06097 Halle, Germany,1 Institut für Medizinische Immunologie, Martin-Luther-Universität Halle-Wittenberg, 06097 Halle, Germany,2 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 947203

Received 16 November 2004/ Returned for modification 8 February 2005/ Accepted 22 February 2005

Epigenetic inactivation of the RASSF1A tumor suppressor by CpG island methylation was frequently detected in cancer. However, the mechanisms of this aberrant DNA methylation are unknown. In the RASSF1A promoter, we characterized four Sp1 sites, which are frequently methylated in cancer. We examined the functional relationship between DNA methylation, histone modification, Sp1 binding, and RASSF1A expression in proliferating human mammary epithelial cells. With increasing passages, the transcription of RASSF1A was dramatically silenced. This inactivation was associated with deacetylation and lysine 9 trimethylation of histone H3 and an impaired binding of Sp1 at the RASSF1A promoter. In mammary epithelial cells that had overcome a stress-associated senescence barrier, a spreading of DNA methylation in the CpG island promoter was observed. When the RASSF1A-silenced cells were treated with inhibitors of DNA methyltransferase and histone deacetylase, binding of Sp1 and expression of RASSF1A reoccurred. In summary, we observed that histone H3 deacetylation and H3 lysine 9 trimethylation occur in the same time window as gene inactivation and precede DNA methylation. Our data suggest that in epithelial cells, histone inactivation may trigger de novo DNA methylation of the RASSF1A promoter and this system may serve as a model for CpG island inactivation of tumor suppressor genes.

* Corresponding author. Mailing address: Institut für Humangenetik und Medizinische Biologie, Martin-Luther-Universität Halle-Wittenberg, Magdeburger Straße 2, 06097 Halle, Germany. Phone: 49-345-557-4537. Fax: 49-345-557-4293. E-mail: reinhard.dammann{at}medizin.uni-halle.de.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, May 2005, p. 3923-3933, Vol. 25, No. 10
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.10.3923-3933.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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