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

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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

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Nasipak, B. T., Padilla-Benavides, T., Green, K. M., Leszyk, J. D., Mao, W., Konda, S., ... Imbalzano, A. N. (2015). Opposing calcium-dependent signalling pathways control skeletal muscle differentiation by regulating a chromatin remodelling enzyme. Nature communications, 6, [7441]. https://doi.org/10.1038/ncomms8441