TY - JOUR
T1 - Opposing calcium-dependent signalling pathways control skeletal muscle differentiation by regulating a chromatin remodelling enzyme
AU - Nasipak, Brian T.
AU - Padilla-Benavides, Teresita
AU - Green, Karin M.
AU - Leszyk, John D.
AU - Mao, Wenjie
AU - Konda, Silvana
AU - Sif, Saïd
AU - Shaffer, Scott A.
AU - Ohkawa, Yasuyuki
AU - Imbalzano, Anthony N.
N1 - Funding Information:
We thank G. Hager and G. Pavlath for plasmids, and C. Emerson, P. Jones, K. Imbalzano, Q. Wu, S. LeBlanc and R. Barutcu for their critical reading of the manuscript. This work was funded by NIH grant GM56244. The MF20 and F5D monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank, created by the NICHD and maintained at the University of Iowa, Department of Biology, Iowa City, IA 52242, USA.
Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/6/17
Y1 - 2015/6/17
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms8441
DO - 10.1038/ncomms8441
M3 - Article
C2 - 26081415
AN - SCOPUS:84935834062
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 7441
ER -