title: Opposing calcium-dependent signalling pathways control skeletal muscle differentiation by regulating a chromatin remodelling enzyme.
abstract: Calcium signalling is important for differentiation-dependent gene expression, but is also involved in other cellular functions. Therefore, mechanisms must exist to distinguish calcium signalling relevant to differentiation. Calcineurin is a calcium-regulated phosphatase that is required for myogenic gene expression and skeletal muscle differentiation. Here, we demonstrate that inhibition of calcineurin blocks chromatin remodelling and that the Brg1 ATPase of the SWI/SNF chromatin remodelling enzyme, which is required for the activation of myogenic gene expression, is a calcineurin substrate. Furthermore, we identify the calcium-regulated classical protein kinase C β (PKCβ) as a repressor of myogenesis and as the enzyme that opposes calcineurin function. Replacement of endogenous Brg1 with a phosphomimetic mutant in primary myoblasts inhibits myogenesis, whereas replacement with a non-phosphorylatable mutant allows myogenesis despite inhibition of calcineurin signalling, demonstrating the functionality of calcineurin/PKC-modified residues. Thus, the Brg1 chromatin remodelling enzyme integrates two antagonistic calcium-dependent signalling pathways that control myogenic differentiation.
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Nasipak
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
authors.forename: Teresita
authors.initials: T
authors.lastname: Padilla-Benavides
authors.affiliation: Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Green
authors.affiliation: Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Leszyk
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Mao
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
authors.forename: Silvana
authors.initials: S
authors.lastname: Konda
authors.affiliation: Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, Ohio 43210, USA.|Department of Biological and Environmental Sciences, College of Arts and Sciences, Qatar University, PO Box 2713, Doha, Qatar.
authors.forename: Saïd
authors.initials: S
authors.lastname: Sif
authors.affiliation: Proteomics and Mass Spectrometry Facility, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shaffer
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.|Department Advanced Medical Initiatives, JST-CREST, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi Fukuoka 812-8582, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ohkawa
authors.affiliation: Department of Cell and Developmental Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Imbalzano
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D020013:Calcium Signaling; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology; D009687:Nuclear Proteins / Q000378:metabolism*; D064546:Protein Kinase C beta / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; D064546:Protein Kinase C beta; D019703:Calcineurin; C513194:Smarca4 protein, mouse; D004265:DNA Helicases