Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle
| Autor: | Bernard J. Jasmin, John A. Lunde, Olga Lozynska, Caroline Ketterer, Tejvir S. Khurana, Kelly J. Perkins, Utpal Basu, Neal A. Rubinstein, Murat T. Budak, Santhosh M. Baby |
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| Rok vydání: | 2007 |
| Předmět: |
Chromatin Immunoprecipitation
Utrophin animal diseases Molecular Sequence Data Repressor Mice medicine Animals Humans Myocyte Gene Silencing RNA Messenger Muscular dystrophy Muscle Skeletal Promoter Regions Genetic Molecular Biology Psychological repression Base Sequence Models Genetic biology Gene Transfer Techniques Gene Expression Regulation Developmental Skeletal muscle Extremities Articles Cell Biology musculoskeletal system medicine.disease GA-Binding Protein Transcription Factor Molecular biology DNA-Binding Proteins Repressor Proteins Chromosome Pairing Drosophila melanogaster medicine.anatomical_structure biology.protein Dystrophin Chromatin immunoprecipitation Protein Binding |
| Zdroj: | Molecular Biology of the Cell. 18:2864-2872 |
| ISSN: | 1939-4586 1059-1524 |
| DOI: | 10.1091/mbc.e06-12-1069 |
| Popis: | 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 GABPα/β 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. |
| Databáze: | OpenAIRE |
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