ROLE OF G9A IN SKELETAL MYOGENESIS

Abstract

Sarcomeres are the basic contractile unit of striated muscle and is essential for muscle contractile function such that mutations in sarcomeric proteins underlie skeletal muscle disease and dysfunction. Here, we provide evidence that the lysine methyltransferase G9a represses expression of several sarcomeric genes, whereby over-expression of G9a disrupts sarcomere integrity of skeletal muscle cells. This inhibition is mediated by G9a catalyzation of repressive histone methylation marks at sarcomeric gene promoters. It also associates with MEF2C, a transcription factor essential for sarcomere gene expression, and enhances the interaction with co-repressor HDAC5. This occurs through blocking of calcium signalling-dependent phosphorylation and cytoplasmic export of HDAC5. Furthermore, we show that G9a over-expression in Drosophila melanogaster results in a perturbation of muscle function by dysregulation of sarcomere genes and mitochondria activity. These results demonstrate epigenetic control of sarcomere assembly and identify new therapeutic avenues for myopathies arising from compromised muscle function.