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J. Biol. Chem., Vol. 283, Issue 35, 23692-23700, August 29, 2008

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Differential Cooperation between Heterochromatin Protein HP1 Isoforms and MyoD in Myoblasts^*

Hakima Yahi¹², Lauriane Fritsch¹, Ophelie Philipot³, Valentina Guasconi, Mouloud Souidi, Philippe Robin, Anna Polesskaya, Regine Losson, Annick Harel-Bellan, and Slimane Ait-Si-Ali⁴

From the Institut André Lwoff, CNRS, FRE 2944, 7 rue Guy Moquet, 94800 Villejuif, Université Paris-Sud, Villejuif F-94801, France and the Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 and INSERM U 596, Université Louis Pasteur, Collège de France, F-67404 Illkirch, France

Mechanisms of transcriptional repression are important during cell differentiation. Mammalian heterochromatin protein 1 isoforms HP1, HP1β, and HP1 play important roles in the regulation of chromatin structure and function. We explored the possibility of different roles for the three HP1 isoforms in an integrated system, skeletal muscle terminal differentiation. In this system, terminal differentiation is initiated by the transcription factor MyoD, whose target genes remain mainly silent until myoblasts are induced to differentiate. Here we show that HP1 and HP1β isoforms, but not HP1, interact with MyoD in myoblasts. This interaction is direct, as shown using recombinant proteins in vitro. A gene reporter assay revealed that HP1 and HP1β, but not HP1, inhibit MyoD transcriptional activity, suggesting a model in which MyoD could serve as a bridge between nucleosomes and chromatin-binding proteins such as HDACs and HP1. Chromatin immunoprecipitation assays show a preferential recruitment of HP1 proteins on MyoD target genes in proliferating myoblasts. Finally, modulation of HP1 protein level impairs MyoD target gene expression and muscle terminal differentiation. Together, our data show a nonconventional interaction between HP1 and a tissue-specific transcription factor, MyoD. In addition, they strongly suggest that HP1 isoforms play important roles during muscle terminal differentiation in an isoform-dependent manner.

Received for publication, April 4, 2008 , and in revised form, June 25, 2008.

^* This work was supported by the Association Française contre les Myopathies, the Fondation Bettencourt-Schueller, the Ligue Nationale contre le Cancer, the Association pour la Recherche sur le Cancer, Ministèredela Recherche ACI-Jeunes Chercheurs Décision 04375, the CNRS, Grant LSHG-CT-2004-502950 from the European Union 6th Framework program (to A. H.-B.), and the Université Paris-Sud Orsay. 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 four supplemental figures. We dedicate this work to the memory of Hélène Richard-Foy.

¹ These authors contributed equally to this work.

² Recipient of a fellowship from the Ligue Nationale contre le Cancer.

³ Recipient of a fellowship from the Ministère de la Recherche.

⁴ To whom correspondence should be addressed. Tel.: 33-1-4958-3384; Fax: 33-1-4958-3307; E-mail: aitsiali{at}vjf.cnrs.fr.

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