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Vol. 18, Issue 8, 2864-2872, August 2007

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Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle

Kelly J. Perkins^*,, Utpal Basu^*, Murat T. Budak^*, Caroline Ketterer^*, Santhosh M. Baby^*, Olga Lozynska^*, John A. Lunde, Bernard J. Jasmin, Neal A. Rubinstein^*, and Tejvir S. Khurana^*

*Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085; and Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada

Submitted December 4, 2006; Revised May 4, 2007; Accepted May 7, 2007
Monitoring Editor: William Tansey

Utrophin is the autosomal homologue of dystrophin, the protein product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin expression is temporally and spatially regulated being developmentally down-regulated perinatally and enriched at neuromuscular junctions (NMJs) in adult muscle. Synaptic localization of utrophin occurs in part by heregulin-mediated extracellular signal-regulated kinase (ERK)-phosphorylation, leading to binding of GABP/ to the N-box/EBS and activation of the major utrophin promoter-A expressed in myofibers. However, molecular mechanisms contributing to concurrent extrasynaptic silencing that must occur to achieve NMJ localization are unknown. We demonstrate that the Ets-2 repressor factor (ERF) represses extrasynaptic utrophin-A in muscle. Gel shift and chromatin immunoprecipitation studies demonstrated physical association of ERF with the utrophin-A promoter N-box/EBS site. ERF overexpression repressed utrophin-A promoter activity; conversely, small interfering RNA-mediated ERF knockdown enhanced promoter activity as well as endogenous utrophin mRNA levels in cultured muscle cells in vitro. Laser-capture microscopy of tibialis anterior NMJ and extrasynaptic transcriptomes and gene transfer studies provide spatial and direct evidence, respectively, for ERF-mediated utrophin repression in vivo. Together, these studies suggest "repressing repressors" as a potential strategy for achieving utrophin up-regulation in DMD, and they provide a model for utrophin-A regulation in muscle.

Present address: Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, United Kingdom.

Address correspondence to: Tejvir S. Khurana (tsk{at}mail.med.upenn.edu).

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