G9a inhibits MEF2C activity to control sarcomere assembly.
In this study, we demonstrate that the lysine methyltransferase G9a inhibits sarcomere organization through regulation of the MEF2C-HDAC5 regulatory axis. Sarcomeres are essential for muscle contractile function. Presently, skeletal muscle disease and dysfunction at the sarcomere level has been associated with mutations of sarcomere proteins. This study provides evidence that G9a represses expression of several sarcomere genes and its over-expression disrupts sarcomere integrity of skeletal muscle cells. G9a inhibits MEF2C transcriptional activity that is essential for expression of sarcomere genes. Through protein interaction assays, we demonstrate that G9a interacts with MEF2C and its co-repressor HDAC5. In the presence of G9a, calcium signaling-dependent phosphorylation and export of HDAC5 to the cytoplasm is blocked which likely results in enhanced MEF2C-HDAC5 association. Activation of calcium signaling or expression of constitutively active CaMK rescues G9a-mediated repression of HDAC5 shuttling as well as sarcomere gene expression. Our results demonstrate a novel epigenetic control of sarcomere assembly and identifies new therapeutic avenues to treat skeletal and cardiac myopathies arising from compromised muscle function.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 117456, Singapore.
Jin Rong
JR
Ow
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
Monica
M
Palanichamy Kala
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
Vinay Kumar
VK
Rao
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 117456, Singapore.
Min Hee
MH
Choi
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
Narendra
N
Bharathy
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 117456, Singapore.
Reshma
R
Taneja
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