Epigenetic Changes Governing Expression in Denervated Skeletal Muscle.

The gene encodes the α-subunit of the voltage-gated cardiac sodium channel (Na1.5), a key player in cardiac action potential depolarization. Genetic variants in protein-coding regions of the human have been largely associated with inherited cardiac arrhythmias. Increasing evidence also suggests that aberrant expression of the gene could increase susceptibility to arrhythmogenic diseases, but the mechanisms governing expression are not yet well understood. To gain insights into the molecular basis of gene regulation, we used rat gastrocnemius muscle four days following denervation, a process well known to stimulate expression. Our results show that denervation of rat skeletal muscle induces the expression of the adult cardiac isoform. RNA-seq experiments reveal that denervation leads to significant changes in the transcriptome, with amongst the fifty top upregulated genes. Consistent with this increase in expression, ChIP-qPCR assays show enrichment of H3K27ac and H3K4me3 and binding of the transcription factor Gata4 near the promoter region. Also, Gata4 mRNA levels are significantly induced upon denervation. Genome-wide analysis of H3K27ac by ChIP-seq suggest that a super enhancer recently described to regulate in cardiac tissue is activated in response to denervation. Altogether, our experiments reveal that similar mechanisms regulate the expression of in denervated muscle and cardiac tissue, suggesting a conserved pathway for expression among striated muscles.