title: Global MEF2 target gene analysis in cardiac and skeletal muscle reveals novel regulation of DUSP6 by p38MAPK-MEF2 signaling.
abstract: MEF2 plays a profound role in the regulation of transcription in cardiac and skeletal muscle lineages. To define the overlapping and unique MEF2A genomic targets, we utilized ChIP-exo analysis of cardiomyocytes and skeletal myoblasts. Of the 2783 and 1648 MEF2A binding peaks in skeletal myoblasts and cardiomyocytes, respectively, 294 common binding sites were identified. Genomic targets were compared to differentially expressed genes in RNA-seq analysis of MEF2A depleted myogenic cells, revealing two prominent genetic networks. Genes largely associated with muscle development were down-regulated by loss of MEF2A while up-regulated genes reveal a previously unrecognized function of MEF2A in suppressing growth/proliferative genes. Several up-regulated (Tprg, Mctp2, Kitl, Prrx1, Dusp6) and down-regulated (Atp1a2, Hspb7, Tmem182, Sorbs2, Lmod3) MEF2A target genes were chosen for further investigation. Interestingly, siRNA targeting of the MEF2A/D heterodimer revealed a somewhat divergent role in the regulation of Dusp6, a MAPK phosphatase, in cardiac and skeletal myogenic lineages. Furthermore, MEF2D functions as a p38MAPK-dependent repressor of Dusp6 in myoblasts. These data illustrate that MEF2 orchestrates both common and non-overlapping programs of signal-dependent gene expression in skeletal and cardiac muscle lineages.
authors.affiliation: Department of Biology, York University, 4700 Keele Street Toronto, Ontario, M3J 1P3 Canada Muscle Health Research Centre (MHRC), York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada Centre for Research on Biomolecular Interactions (CRBI), 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wales
authors.affiliation: Department of Biology, York University, 4700 Keele Street Toronto, Ontario, M3J 1P3 Canada Muscle Health Research Centre (MHRC), York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada Centre for Research on Biomolecular Interactions (CRBI), 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Hashemi
authors.affiliation: Ottawa Institute of Systems Biology, University of Ottawa, Health Sciences Campus, 451 Smyth Road, Ottawa, Ontario, K1H 8M5 Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Blais
authors.affiliation: Department of Biology, York University, 4700 Keele Street Toronto, Ontario, M3J 1P3 Canada Muscle Health Research Centre (MHRC), York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada Centre for Research on Biomolecular Interactions (CRBI), 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada Centre for Research in Mass Spectrometry (CRMS), York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3 Canada jmcderm@yorku.ca.
authors.forename: John C
authors.initials: JC
authors.lastname: McDermott
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D053263:Gene Regulatory Networks; D020935:MAP Kinase Signaling System; D064326:MEF2 Transcription Factors / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D064326:MEF2 Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D054642:Dual Specificity Phosphatase 6