title: MEF2 transcription factors regulate distinct gene programs in mammalian skeletal muscle differentiation.
abstract: Skeletal muscle differentiation requires precisely coordinated transcriptional regulation of diverse gene programs that ultimately give rise to the specialized properties of this cell type. In Drosophila, this process is controlled, in part, by MEF2, the sole member of an evolutionarily conserved transcription factor family. By contrast, vertebrate MEF2 is encoded by four distinct genes, Mef2a, -b, -c, and -d, making it far more challenging to link this transcription factor to the regulation of specific muscle gene programs. Here, we have taken the first step in molecularly dissecting vertebrate MEF2 transcriptional function in skeletal muscle differentiation by depleting individual MEF2 proteins in myoblasts. Whereas MEF2A is absolutely required for proper myoblast differentiation, MEF2B, -C, and -D were found to be dispensable for this process. Furthermore, despite the extensive redundancy, we show that mammalian MEF2 proteins regulate a significant subset of nonoverlapping gene programs. These results suggest that individual MEF2 family members are able to recognize specific targets among the entire cohort of MEF2-regulated genes in the muscle genome. These findings provide opportunities to modulate the activity of MEF2 isoforms and their respective gene programs in skeletal muscle homeostasis and disease.
authors.affiliation: From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Nelsa L
authors.initials: NL
authors.lastname: Estrella
authors.affiliation: From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Cody A
authors.initials: CA
authors.lastname: Desjardins
authors.affiliation: From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Nocco
authors.affiliation: From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Clark
authors.affiliation: From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Yevgeniy
authors.initials: Y
authors.lastname: Maksimenko
authors.affiliation: From the Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215 fnaya@bu.edu.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Naya
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000235:genetics*; D002522:Chlorocebus aethiops; D004330:Drosophila / Q000235:genetics / Q000254:growth & development; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D064326:MEF2 Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008322:Mammals / Q000235:genetics / Q000254:growth & development; D051379:Mice; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000254:growth & development*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D064326:MEF2 Transcription Factors; D020033:Protein Isoforms
keywords: Differentiation; Myogenesis; RNA Interference (RNAi); Transcription Factor; Transcriptomics