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J. Biol. Chem., Vol. 282, Issue 47, 34535-34541, November 23, 2007

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The Krüppel-associated Box Repressor Domain Can Trigger de Novo Promoter Methylation during Mouse Early Embryogenesis^*

Maciej Wiznerowicz¹, Johan Jakobsson², Jolanta Szulc, Shunyao Liao, Alexandra Quazzola, Friedrich Beermann^¶, Patrick Aebischer, and Didier Trono³

From the School of Life Sciences, "Frontiers in Genetics" National Center for Competence in Research, and ^¶Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland

The Krüppel-associated box (KRAB) domain is a transcriptional repression module responsible for the DNA binding-dependent gene silencing activity of hundreds of vertebrate zinc finger proteins. We previously exploited KRAB-mediated repression within the context of a tet repressor-KRAB fusion protein and of lentiviral vectors to create a method of external gene control. We demonstrated that with this system transcriptional silencing was fully reversible in cell culture as well as in vivo. Here we reveal that, in sharp contrast, KRAB-mediated repression results in irreversible gene silencing through promoter DNA methylation if it acts during the first few days of mouse development.

Received for publication, July 18, 2007 , and in revised form, September 24, 2007.

^* This work was supported in part by grants from the Swiss National Science Foundation and the European Union (to D. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Present address: Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115.

² Supported by a post-doctoral fellowship from the Swedish Research Council.

³ To whom correspondence should be addressed: Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, EPFL SV-DO, Building AAB, Station 15, CH 1015 Lausanne, Switzerland. Tel.: 41-21-693-1751; Fax: 41-21-693-1635; E-mail: dider.trono{at}epfl.ch.

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