Opposing calcium-dependent signalling pathways control skeletal muscle differentiation by regulating a chromatin remodelling enzyme
Department of Cell and Developmental Biology; Proteomics and Mass Spectrometry Facility; Department of Biochemistry and Molecular Pharmacology
Cell Biology | Computational Biology | Developmental Biology
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 beta (PKCbeta) 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.
Biological sciences, Cell biology, Developmental biology
DOI of Published Version
Nat Commun. 2015 Jun 17;6:7441. doi: 10.1038/ncomms8441. Link to article on publisher's site
Nasipak, Brian T.; Padilla-Benavides, Teresita; Green, Karin M.; Leszyk, John D.; Mao, Wenjie; Konda, Silvana; Sif, Said; Shaffer, Scott A.; Ohkawa, Yasuyuki; and Imbalzano, Anthony N., "Opposing calcium-dependent signalling pathways control skeletal muscle differentiation by regulating a chromatin remodelling enzyme" (2015). Cell and Developmental Biology Publications. 168.