title: Regulation of Hspb7 by MEF2 and AP-1: implications for Hspb7 in muscle atrophy.
abstract: Mycocyte enhancer factor 2 (MEF2) and activator protein 1 (AP-1) transcription complexes have been individually implicated in myogenesis, but their genetic interaction has not previously been addressed. Using MEF2A, c-Jun and Fra-1 chromatin immunoprecipitation sequencing (ChIP-seq) data and predicted AP-1 consensus motifs, we identified putative common MEF2 and AP-1 target genes, several of which are implicated in regulating the actin cytoskeleton. Because muscle atrophy results in remodelling or degradation of the actin cytoskeleton, we characterized the expression of putative MEF2 and AP-1 target genes (Dstn, Flnc, Hspb7, Lmod3 and Plekhh2) under atrophic conditions using dexamethasone (Dex) treatment in skeletal myoblasts. Heat shock protein b7 (Hspb7) was induced by Dex treatment and further analyses revealed that loss of MEF2A using siRNA prevented Dex-regulated induction of Hspb7. Conversely, ectopic Fra-2 or c-Jun expression reduced Dex-mediated upregulation of Hspb7 whereas AP-1 depletion enhanced Hspb7 expression. In vivo, expression of Hspb7 and other autophagy-related genes was upregulated in response to atrophic conditions in mice. Manipulation of Hspb7 levels in mice also impacted gross muscle mass. Collectively, these data indicate that MEF2 and AP-1 confer antagonistic regulation of Hspb7 gene expression in skeletal muscle, with implications for autophagy and muscle atrophy.
authors.affiliation: Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3.|Muscle Health Research Centre (MHRC), York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3.|Centre for Research in Biomolecular Interactions (CRBI), 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3.
authors.forename: Stephanie Wales
authors.initials: SW
authors.lastname: Tobin
authors.affiliation: Ottawa Institute of Systems Biology, University of Ottawa, Health Sciences Campus, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Dabo
authors.initials: D
authors.lastname: Yang
authors.affiliation: Ottawa Institute of Systems Biology, University of Ottawa, Health Sciences Campus, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: John
authors.initials: J
authors.lastname: Girgis
authors.affiliation: Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3.|Muscle Health Research Centre (MHRC), York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3.|Centre for Research in Biomolecular Interactions (CRBI), 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3.
authors.forename: Ali
authors.initials: A
authors.lastname: Farahzad
authors.affiliation: Ottawa Institute of Systems Biology, University of Ottawa, Health Sciences Campus, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Blais
authors.affiliation: Department of Biology, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3 jmcderm@yorku.ca.|Muscle Health Research Centre (MHRC), York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3.|Centre for Research in Biomolecular Interactions (CRBI), 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3.|Centre for Research in Mass Spectrometry (CRMS), York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3.
authors.forename: John C
authors.identifier: 0000-0001-9696-8929
authors.initials: JC
authors.lastname: McDermott
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology; D051921:Fos-Related Antigen-2 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000235:genetics* / Q000473:pathology*; D009929:Organ Size / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D051921:Fos-Related Antigen-2; D055551:HSP27 Heat-Shock Proteins; C000613262:HSPB7 protein, mouse; D064326:MEF2 Transcription Factors; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D003907:Dexamethasone
keywords: AP-1; Autophagy; MEF2; Myogenesis