Opposing calcium-dependent signalling pathways control skeletal muscle differentiation by regulating a chromatin remodelling enzyme

Brian T. Nasipak, Teresita Padilla-Benavides, Karin M. Green, John D. Leszyk, Wenjie Mao, Silvana Konda, Saïd Sif, Scott A. Shaffer, Yasuyuki Ohkawa, Anthony N. Imbalzano

    Research output: Contribution to journalArticlepeer-review

    29 Citations (Scopus)

    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.

    Original languageEnglish
    Article number7441
    JournalNature communications
    Volume6
    DOIs
    Publication statusPublished - Jun 17 2015

    All Science Journal Classification (ASJC) codes

    • General Chemistry
    • General Biochemistry,Genetics and Molecular Biology
    • General Physics and Astronomy

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