Abstract
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.
Highlights
Consistent with their central role in regulating myocyte enhancer factor 2 (MEF2) activity, class II histone deacetylases (HDACs) regulate fiber type specific programs that are MEF2-dependent[22,23]
Upon treatment with UNC0638, expression of sarcomere genes was increased in C2C12 cells and primary myoblasts (Fig. 1c, Supplementary Fig. 1b), whereas global H3K9me[2] was reduced, indicating that the methyltransferase activity of G9a is important for repression of sarcomeric genes
The results of this study reveal for the first time that G9a epigenetically controls structural elements in skeletal muscle
Summary
Consistent with their central role in regulating MEF2 activity, class II HDACs regulate fiber type specific programs that are MEF2-dependent[22,23] They mediate the repressive effects on MEF2-dependent structural and contractile genes in vivo[24]. As such, increased expression of class II HDACs in skeletal muscle are associated with congenital myopathies[25] that display disruption of sarcomere assembly and reduced expression of MEF2 target genes such as Lmod[326]. Another co-repressor that has been implicated in the regulation of muscle structural and sarcomere genes is G9a. These studies provide evidence that G9a forms a repressive complex with MEF2C and HDAC5 to epigenetically control sarcomere organization
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